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Find video protocols related to scientific articles indexed in Pubmed.
Vivid, full-color aluminum plasmonic pixels.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 09-15-2014
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Aluminum is abundant, low in cost, compatible with complementary metal-oxide semiconductor manufacturing methods, and capable of supporting tunable plasmon resonance structures that span the entire visible spectrum. However, the use of Al for color displays has been limited by its intrinsically broad spectral features. Here we show that vivid, highly polarized, and broadly tunable color pixels can be produced from periodic patterns of oriented Al nanorods. Whereas the nanorod longitudinal plasmon resonance is largely responsible for pixel color, far-field diffractive coupling is used to narrow the plasmon linewidth, enabling monochromatic coloration and significantly enhancing the far-field scattering intensity of the individual nanorod elements. The bright coloration can be observed with p-polarized white light excitation, consistent with the use of this approach in display devices. The resulting color pixels are constructed with a simple design, are compatible with scalable fabrication methods, and provide contrast ratios exceeding 100:1.
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Potential of ZrO clusters as replacement Pd catalyst.
J Chem Phys
PUBLISHED: 07-24-2014
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Atomic clusters with specific size and composition and mimicking the chemistry of elements in the periodic table are commonly known as superatoms. It has been suggested that superatoms could be used to replace elements that are either scarce or expensive. Based on a photoelectron spectroscopy experiment of negatively charged ions, Castleman and co-workers [Proc. Natl. Acad. Sci. U.S.A. 107, 975 (2010)] have recently shown that atoms of Ni, Pd, and Pt which are well known for their catalytic properties, have the same electronic structure as their counterpart isovalent diatomic species, TiO, ZrO, and WC, respectively. Based on this similarity they have suggested that ZrO, for example, could be a replacement catalyst for Pd. Since catalysts are seldom single isolated atoms, one has to demonstrate that clusters of ZrO also have the same electronic structure as same sized Pd clusters. To examine if this is indeed the case, we have calculated the geometries, electronic structure, electron affinity, ionization potential, and hardness of Pdn and (ZrO)n clusters (n = 1-5). We further studied the reaction of these clusters in neutral and charged forms with H2, O2, and CO and found it to be qualitatively different in most cases. These results obtained using density functional theory with hybrid B3LYP functional do not support the view that ZrO clusters can replace Pd as a catalyst.
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The plasticity of inflammatory monocyte responses to the inflamed central nervous system.
Cell. Immunol.
PUBLISHED: 06-13-2014
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Over the last three decades it has become increasingly clear that monocytes, originally thought to have fixed, stereotypic responses to foreign stimuli, mediate exquisitely balanced protective and pathogenic roles in disease and immunity. This balance is crucial in core functional organs, such as the central nervous system (CNS), where minor changes in neuronal microenvironments and the production of immune factors can result in significant disease with fatal consequences or permanent neurological sequelae. Viral encephalitis and multiple sclerosis are examples of important human diseases in which the pathogenic contribution of monocytes recruited from the bone marrow plays a critical role in the clinical expression of disease, as they differentiate into macrophage or dendritic cells in the CNS to carry out effector functions. While antigen-specific lymphocyte populations are central to the adaptive immune response in both cases, in viral encephalitis a prominent macrophage infiltration may mediate immunopathological damage, seizure induction, and death. However, the autoimmune response to non-replicating, non-infectious, but abundant, self antigen has a different disease progression, associated with differentiation of significant numbers of infiltrating monocytes into dendritic cells in the CNS. Whilst a predominant presence of macrophages or dendritic cells in the inflamed CNS in viral encephalitis or multiple sclerosis is well described, the way in which the inflamed CNS mobilizes monocytes in the bone marrow to migrate to the CNS and the key drivers that lead to these specific differentiation pathways in vivo are not well understood. Here we review the current understanding of factors facilitating inflammatory monocyte generation, migration and entry into the brain, as well as their differentiation towards macrophages or dendritic cells in viral and autoimmune disease in relation to their respective disease outcomes.
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Determinants of increased opioid-related mortality in the United States and Canada, 1990-2013: a systematic review.
Am J Public Health
PUBLISHED: 06-12-2014
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We review evidence of determinants contributing to increased opioid-related mortality in the United States and Canada between 1990 and 2013. We identified 17 determinants of opioid-related mortality and mortality increases that we classified into 3 categories: prescriber behavior, user behavior and characteristics, and environmental and systemic determinants. These determinants operate independently but interact in complex ways that vary according to geography and population, making generalization from single studies inadvisable. Researchers in this area face significant methodological difficulties; most of the studies in our review were ecological or observational and lacked control groups or adjustment for confounding factors; thus, causal inferences are difficult. Preventing additional opioid-related mortality will likely require interventions that address multiple determinants and are tailored to specific locations and populations.
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Defective Inflammatory Monocyte Development in IRF8-Deficient Mice Abrogates Migration to the West Nile Virus-Infected Brain.
J Innate Immun
PUBLISHED: 06-02-2014
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IRF8 (interferon-regulatory factor-8) plays a critical role in regulating myeloid cell differentiation. However, the role of this transcription factor in the development of Ly6C+ inflammatory monocytes and their migration to the infected brain has not been examined. We have previously shown that West Nile virus (WNV) infection of wild-type (WT) mice triggers a significant increase in numbers of Ly6C+ monocytes in the bone marrow. These cells traffic via the blood to the infected brain, where they give rise to proinflammatory macrophages. Here, we show that WNV-infected IRF8-deficient (IRF8-/-) mice had significantly reduced numbers of Ly6C+ monocytes in the periphery, with few of these cells found in the blood. Furthermore, low numbers of inflammatory monocyte-derived macrophages were observed in the brains of IRF8-/- mice throughout infection. Adoptive transfer of IRF8-/- Ly6C+ monocytes demonstrated that these cells were intrinsically unable to traffic to the inflamed brain. Low expression of the chemokine receptor CCR2 and integrin VLA-4 by IRF8-/- monocytes likely contributed to this defect, as the interactions between these proteins and their ligands are critical for monocyte egress and migration to inflammatory foci. These data highlight a critical role for IRF8 in inflammatory monocyte differentiation and migration during WNV infection. © 2014 S. Karger AG, Basel.
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[Implicit value judgments in the measurement of health inequalities].
Rev. Panam. Salud Publica
PUBLISHED: 05-30-2014
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Quantitative estimates of the magnitude, direction, and rate of change of health inequalities play a crucial role in creating and assessing policies aimed at eliminating the disproportionate burden of disease in disadvantaged populations. It is generally assumed that the measurement of health inequalities is a value-neutral process, providing objective data that are then interpreted using normative judgments about whether a particular distribution of health is just, fair, or socially acceptable.
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Nonclinical Safety Biomarkers of Drug-induced Vascular Injury: Current Status and Blueprint for the Future.
Toxicol Pathol
PUBLISHED: 04-28-2014
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Better biomarkers are needed to identify, characterize, and/or monitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG developed a strategy based on the premise that biomarkers of DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic lexicon for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, and confirmation of target localization using immunohistochemistry and in situ hybridization are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI.
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Therapeutic inflammatory monocyte modulation using immune-modifying microparticles.
Sci Transl Med
PUBLISHED: 01-17-2014
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Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3-mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate-induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.
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Immunomodulatory effects of bone marrow-derived mesenchymal stem cells on pro-inflammatory cytokine-stimulated human corneal epithelial cells.
PLoS ONE
PUBLISHED: 01-01-2014
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To investigate the modulatory effect of rat bone marrow mesenchymal stem cells (MSC) on human corneal epithelial cells (HCE-T) stimulated with pro-inflammatory cytokines interferon gamma (IFN-?) and tumor necrosis factor alpha (TNF-?) in an in vitro co-cultured model.
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The role of CXCR3 in DSS-induced colitis.
PLoS ONE
PUBLISHED: 01-01-2014
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Inflammatory bowel disease (IBD) is a group of disorders that are characterized by chronic, uncontrolled inflammation in the intestinal mucosa. Although the aetiopathogenesis is poorly understood, it is widely believed that IBD stems from a dysregulated immune response towards otherwise harmless commensal bacteria. Chemokines induce and enhance inflammation through their involvement in cellular trafficking. Reducing or limiting the influx of these proinflammatory cells has previously been demonstrated to attenuate inflammation. CXCR3, a chemokine receptor in the CXC family that binds to CXCL9, CXCL10 and CXCL11, is strongly overexpressed in the intestinal mucosa of IBD patients. We hypothesised that CXCR3 KO mice would have impaired cellular trafficking, thereby reducing the inflammatory insult by proinflammatory cell and attenuating the course of colitis. To investigate the role of CXCR3 in the progression of colitis, the development of dextran sulfate sodium (DSS)-induced colitis was investigated in CXCR3-/- mice over 9 days. This study demonstrated attenuated DSS-induced colitis in CXCR3-/- mice at both the macroscopic and microscopic level. Reduced colitis correlated with lower recruitment of neutrophils (p = 0.0018), as well as decreased production of IL-6 (p<0.0001), TNF (p = 0.0038), and IFN-? (p = 0.0478). Overall, our results suggest that CXCR3 plays an important role in recruiting proinflammatory cells to the colon during colitis and that CXCR3 may be a therapeutic target to reduce the influx of proinflammatory cells in the inflamed colon.
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Aluminum for Plasmonics.
ACS Nano
PUBLISHED: 12-04-2013
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Unlike silver and gold, aluminum has material properties that enable strong plasmon resonances spanning much of the visible region of the spectrum and into the ultraviolet. This extended response, combined with its natural abundance, low cost, and amenability to manufacturing processes, makes aluminum a highly promising material for commercial applications. Fabricating Al-based nanostructures whose optical properties correspond with theoretical predictions, however, can be a challenge. In this work, the Al plasmon resonance is observed to be remarkably sensitive to the presence of oxide within the metal. For Al nanodisks, we observe that the energy of the plasmon resonance is determined by, and serves as an optical reporter of, the percentage of oxide present within the Al. This understanding paves the way toward the use of aluminum as a low-cost plasmonic material with properties and potential applications similar to those of the coinage metals.
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Orienting nanoantennas in three dimensions to control light scattering across a dielectric interface.
Nano Lett.
PUBLISHED: 11-14-2013
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The light scattering properties of hemispherical resonant nanoantennas can be used to redirect normal incidence light to propagate within a thin film or thin film-based device, such as a solar cell, for enhanced efficiency. While planar nanoantennas are typically fabricated as simple nanoparticles or nanostructures in the film plane, here we show that a hemispherical nanoantenna with its symmetry axis tilted out of the plane accomplishes this task with far greater efficacy. The amount of light scattered into an underlying dielectric by the electric and magnetic dipole response of oriented nanocups can be more than three times that achieved using symmetric antenna structures.
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The bacteriostatic protein lipocalin 2 is induced in the central nervous system of mice with west nile virus encephalitis.
J. Virol.
PUBLISHED: 10-30-2013
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Lipocalin 2 (Lcn2) is a bacteriostatic factor produced during the innate immune response to bacterial infection. Whether Lcn2 has a function in viral infection is unknown. We investigated the regulation and function of Lcn2 in the central nervous system (CNS) of mice during West Nile virus (WNV) encephalitis. Lcn2 mRNA and protein were induced in the brain by day 5, and this induction increased further by day 7 postinfection but was delayed compared with the induction of the toll-like receptor 3 (TLR3) gene, retinoic acid-inducible gene 1 (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) gene. The Lcn2 mRNA and protein were both found at high levels in the choroid plexus, vascular endothelium, macrophage/microglia, and astrocytes. However, some neuronal subsets contained Lcn2 protein but no detectable mRNA. In Lcn2 knockout (KO) mice, with the exception of CXC motif chemokine 5 (CXCL5), which was significantly more downregulated than in wild-type (WT) mice, expression levels of a number of other host response genes were similar in the two genotypes. The brain from Lcn2 and WT mice with WNV encephalitis contained similar numbers of infiltrating macrophages, granulocytes, and T cells. Lcn2 KO and WT mice had no significant difference in tissue viral loads or survival after infection with different doses of WNV. We conclude that Lcn2 gene expression is induced to high levels in a time-dependent fashion in a variety of cells and regions of the CNS of mice with WNV encephalitis. The function of Lcn2 in the host response to WNV infection remains largely unknown, but our data indicate that it is dispensable as an antiviral or immunoregulatory factor in WNV encephalitis.
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Untreated pain, narcotics regulation, and global health ideologies.
PLoS Med.
PUBLISHED: 04-02-2013
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Pain management is marginalized or ignored, with millions of people worldwide unnecessarily living with untreated pain. Reducing global inequalities in untreated pain requires a concerted global effort, say Veronique Fraser and colleagues, which must attend to the complexity of pain and promote multimodal, multidisciplinary pain management.
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Narrowband photodetection in the near-infrared with a plasmon-induced hot electron device.
Nat Commun
PUBLISHED: 02-25-2013
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In gratings, incident light can couple strongly to plasmons propagating through periodically spaced slits in a metal film, resulting in a strong, resonant absorption whose frequency is determined by the nanostructure periodicity. When a grating is patterned on a silicon substrate, the absorption response can be combined with plasmon-induced hot electron photocurrent generation. This yields a photodetector with a strongly resonant, narrowband photocurrent response in the infrared, limited at low frequencies by the Schottky barrier, not the bandgap of silicon. Here we report a grating-based hot electron device with significantly larger photocurrent responsivity than previously reported antenna-based geometries. The grating geometry also enables more than three times narrower spectral response than observed for nanoantenna-based devices. This approach opens up the possibility of plasmonic sensors with direct electrical readout, such as an on-chip surface plasmon resonance detector driven at a single wavelength.
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Surface-enhanced infrared absorption using individual cross antennas tailored to chemical moieties.
J. Am. Chem. Soc.
PUBLISHED: 02-22-2013
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The development of antenna structures for surface-enhanced infrared absorption spectroscopy (SEIRA) is a topic of intense and growing interest for extending IR spectroscopy to zeptomolar quantities and ultimately to the single-molecule level. Here we show that strong infrared spectroscopic enhancements can be obtained from individual gold nanoantennas using conventional IR spectrometric sources. The antenna structure dimensions can be tuned to enhance the IR modes of specific chemical moieties. Simulations of the electric field intensity in the antenna junction region reveal a maximum SEIRA enhancement factor of more than 12,000. These findings open new opportunities for analyzing IR vibrations of exceptionally small quantities of molecules using widely accessible light sources.
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Impact of selective evidence presentation on judgments of health inequality trends: an experimental study.
PLoS ONE
PUBLISHED: 01-01-2013
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Reducing health inequalities is a key objective for many governments and public health organizations. Whether inequalities are measured on the absolute (difference) or relative (ratio) scale can have a significant impact on judgments about whether health inequalities are increasing or decreasing, but both of these measures are not often presented in empirical studies. In this study we investigated the impact of selective presentation of health inequality measures on judgments of health inequality trends among 40 university undergraduates. We randomized participants to see either a difference or ratio measure of health inequality alongside raw mortality rates in 5 different scenarios. At baseline there were no differences between treatment groups in assessments of inequality trends, but selective exposure to the same raw data augmented with ratio versus difference inequality graphs altered participants assessments of inequality change. When absolute inequality decreased and relative inequality increased, exposure to ratio measures increased the probability of concluding that inequality had increased from 32.5% to 70%, but exposure to difference measures did not (35% vs. 25%). Selective exposure to ratio versus difference inequality graphs thus increased the difference between groups in concluding that inequality had increased from 2.5% (95% CI -9.5% to 14.5%) to 45% (95% CI 29.4 to 60.6). A similar pattern was evident for other scenarios where absolute and relative inequality trends gave conflicting results. In cases where measures of absolute and relative inequality both increased or both decreased, we did not find any evidence that assignment to ratio vs. difference graphs had an impact on assessments of inequality change. Selective reporting of measures of health inequality has the potential to create biased judgments of progress in ameliorating health inequalities.
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IL-22 and non-ELR-CXC chemokine expression in chronic hepatitis B virus-infected liver.
Immunol. Cell Biol.
PUBLISHED: 09-27-2011
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Hepatitis B virus infection is still a major global health problem, despite decades of research. Interleukin (IL)-22 induces acute phase reactants and chemokines, favors anti-microbial defence and protects tissues from damage. IL-22 is important in chronic skin inflammation, but its role in chronic hepatitis B (CHB) is unclear. This study explores the association between intra-hepatic IL-22 expression, its relevant associated cytokines and the severity of liver inflammation/fibrosis in CHB patients. IL-22, IL-17, IL-10, IL-6, non-ELR-CXC chemokines (CXCL-9, CXCL-10, CXCL-11), fibroblast growth factors and Kupffer cell (KC) numbers were measured in patients with CHB (n=65), acute hepatitis B (AHB; n=4), chronic hepatitis C (CHC; n=14) and non-viral hepatitis (n=23), using immunohistochemistry. Expression of IL-22, IL-17, IL-10, IL-6, non-ELR-CXC chemokines and number of KCs in liver tissues were substantially higher in AHB patients than others. In CHB patients, the expression of IL-22, IL-6, CXCL-9 and CXCL-10 were significantly higher with alanine aminotransferase (ALT) levels ? twice the upper limit of normal (ULN), compared with those with ALT levels >twice the ULN, whereas IL-10 and IL-17 showed a reverse pattern. IL-22 was inversely (P<0.01), but IL-17 was positively (P<0.05), correlated with the histological activity index) in these patients, and a significant negative correlation between the fibrosis stage and IL-22 or non-ELR-CXC chemokines was observed. Furthermore, immunofluorescent labeling demonstrated a close spatial association of IL-22, CXCL-9, -10 or -11 in the CHB liver. We speculate that IL-22 and non-ELR-CXC chemokines synergistically may provide protection in liver inflammation/fibrosis during CHB infection.
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Microparticles as immune regulators in infectious disease - an opinion.
Front Immunol
PUBLISHED: 09-06-2011
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Despite their clear relationship to immunology, few existing studies have examined the potential role of microparticles (MP) in infectious disease. MP have a different size range from exosomes and apoptotic bodies, with which they are often grouped and arise by different mechanisms in association with inflammatory cytokine action or stress on the source cell. Infection with pathogens usually leads to the expression of a range of inflammatory cytokines and chemokines, as well as significant stress in both infected and uninfected cells. It is thus reasonable to infer that infection-associated inflammation also leads to MP production. MP are produced by most of the major cell types in the immune system, and appear to be involved at both innate and adaptive levels, potentially serving different functions in each. Thus, they do not appear to have a universal function; instead their functions are source- or stimulus-dependent, although likely to be primarily either pro- or anti-inflammatory. We argue that in infectious diseases, MP may be able to deliver antigen, derived from the biological cargo acquired from their cells of origin, to antigen-presenting cells. Another potential benefit of MP would be to transfer and/or disseminate phenotype and function to target cells. However, MP may also potentially be manipulated, particularly by intracellular pathogens, for survival advantage.
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Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells.
J. Immunol.
PUBLISHED: 08-05-2011
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Ag-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide Ags linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-coupled splenocytes [Ag-SP]) has been demonstrated to be a highly efficient method for inducing peripheral, Ag-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy. In this study, we show that apoptotic Ag-SP accumulate in the splenic marginal zone, where their uptake by F4/80(+) macrophages induces production of IL-10, which upregulates the expression of the immunomodulatory costimulatory molecule PD-L1 that is essential for Ag-SP tolerance induction. Ag-SP infusion also induces T regulatory cells that are dispensable for tolerance induction but required for long-term tolerance maintenance. Collectively, these results indicate that Ag-SP tolerance recapitulates how tolerance is normally maintained in the hematopoietic compartment and highlight the interplay between the innate and adaptive immune systems in the induction of Ag-SP tolerance. To our knowledge, we show for the first time that tolerance results from the synergistic effects of two distinct mechanisms, PD-L1-dependent T cell-intrinsic unresponsiveness and the activation of T regulatory cells. These findings are particularly relevant as this tolerance protocol is currently being tested in a Phase I/IIa clinical trial in new-onset relapsing-remitting multiple sclerosis.
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Effects of ?(2) Agonists, Corticosteroids, and Novel Therapies on Rhinovirus-Induced Cytokine Release and Rhinovirus Replication in Primary Airway Fibroblasts.
J Allergy (Cairo)
PUBLISHED: 07-27-2011
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Rhinovirus-(RV-) induced asthma exacerbations account for high asthma-related health costs and morbidity in Australia. The cellular mechanism underlying this pathology is likely the result of RV-induced nuclear-factor-kappa-B-(NF-?B-) dependent inflammation. NF-?B may also be important in RV replication as inhibition of NF-?B inhibits replication of other viruses such as human immunodeficiency virus and cytomegalovirus. To establish the role of NF-?B inhibitors in RV-induced IL- 6 and IL-8 and RV replication, we used pharmacological inhibitors of NF-?B, and steroids and/or ?(2) agonists were used for comparison. Primary human lung fibroblasts were infected with RV-16 in the presence of NF-?B inhibitors: BAY-117085 and dimethyl fumarate; ?(2) agonist: salmeterol; and/or corticosteroids: dexamethasone; fluticasone. RV-induced IL-6 and IL-8 and RV replication were assessed using ELISAs and virus titration assays. RV replicated and increased IL-6 and IL-8 release. Salmeterol increased, while dexamethasone and fluticasone decreased RV-induced IL-6 and IL-8 (P<0.05). The NF-?B inhibitor BAY-117085 inhibited only RV-induced IL-6 (P<0.05) and dimethyl fumarate did not alter RV-induced IL-6 and IL-8. Dimethylfumarate increased RV replication whilst other drugs did not alter RV replication. These data suggest that inhibition of NF-?B alone is unlikely to be an effective treatment compared to current asthma therapeutics.
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Angle- and spectral-dependent light scattering from plasmonic nanocups.
ACS Nano
PUBLISHED: 07-25-2011
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As optical frequency nanoantennas, reduced-symmetry plasmonic nanoparticles have light-scattering properties that depend strongly on geometry, orientation, and variations in dielectric environment. Here we investigate how these factors influence the spectral and angular dependence of light scattered by Au nanocups. A simple dielectric substrate causes the axial, electric dipole mode of the nanocup to deviate substantially from its characteristic cos(2) ? free space scattering profile, while the transverse, magnetic dipole mode remains remarkably insensitive to the presence of the substrate. Nanoscale irregularities of the nanocup rim and the local substrate permittivity have a surprisingly large effect on the spectral- and angle-dependent light-scattering properties of these structures.
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Mouse intact cardiac myocyte mechanics: cross-bridge and titin-based stress in unactivated cells.
J. Gen. Physiol.
PUBLISHED: 04-08-2011
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A carbon fiber-based cell attachment and force measurement system was used to measure the diastolic stress-sarcomere length (SL) relation of mouse intact cardiomyocytes, before and after the addition of actomyosin inhibitors (2,3-butanedione monoxime [BDM] or blebbistatin). Stress was measured during the diastolic interval of twitching myocytes that were stretched at 100% base length/second. Diastolic stress increased close to linear from 0 at SL 1.85 µm to 4.2 mN/mm(2) at SL 2.1 µm. The actomyosin inhibitors BDM and blebbistatin significantly lowered diastolic stress by ?1.5 mN/mm(2) (at SL 2.1 µm, ?30% of total), suggesting that during diastole actomyosin interaction is not fully switched off. To test this further, calcium sensitivity of skinned myocytes was studied under conditions that simulate diastole: 37°C, presence of Dextran T500 to compress the myofilament lattice to the physiological level, and [Ca(2+)] from below to above 100 nM. Mean active stress was significantly increased at [Ca(2+)] > 55 nM (pCa 7.25) and was ?0.7 mN/mm(2) at 100 nM [Ca(2+)] (pCa 7.0) and ?1.3 mN/mm(2) at 175 nM Ca(2+) (pCa 6.75). Inhibiting active stress in intact cells attached to carbon fibers at their resting SL and stretching the cells while first measuring restoring stress (pushing outward) and then passive stress (pulling inward) made it possible to determine the passive cells mechanical slack SL as ?1.95 µm and the restoring stiffness and passive stiffness of the cells around the slack SL each as ?17 mN/mm(2)/µm/SL. Comparison between the results of intact and skinned cells shows that titin is the main contributor to restoring stress and passive stress of intact cells, but that under physiological conditions, calcium sensitivity is sufficiently high for actomyosin interaction to contribute to diastolic stress. These findings are relevant for understanding diastolic function and for future studies of diastolic heart failure.
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Rhinovirus infection induces extracellular matrix protein deposition in asthmatic and nonasthmatic airway smooth muscle cells.
Am. J. Physiol. Lung Cell Mol. Physiol.
PUBLISHED: 04-01-2011
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Airway remodeling, which includes increases in the extracellular matrix (ECM), is a characteristic feature of asthma and is correlated to disease severity. Rhinovirus (RV) infections are associated with increased risk of asthma development in young children and are the most common cause of asthma exacerbations. We examined whether viral infections can increase ECM deposition and whether this increased ECM modulates cell proliferation and migration. RV infection of nonasthmatic airway smooth muscle (ASM) cells significantly increased the deposition of fibronectin (40% increase, n = 12) and perlecan (80% increase, n = 14), while infection of asthmatic ASM cells significantly increased fibronectin (75% increase, n = 9) and collagen IV (15% increase, n = 9). We then treated the ASM cells with the Toll-like receptor (TLR) agonists polyinosinic:polycytidylic acid, imiquimod, and pure RV RNA and were able to show that the mechanism through which RV induced ECM deposition was via the activation of TLR3 and TLR7/8. Finally, we assessed whether the virus-induced ECM was bioactive by measuring the amount of migration and proliferation of virus-naive cells that seeded onto the ECM. Basically, ECM from asthmatic ASM cells induced twofold greater migration of virus-naive ASM cells than ECM from nonasthmatic ASM cells, and these rates of migration were further increased on RV-modulated ECM. Increased migration on the RV-modulated ECM was not due to increased cell proliferation, as RV-modulated ECM decreased the proliferation of virus-naive cells. Our results suggest that viruses may contribute to airway remodeling through increased ECM deposition, which in turn may contribute to increased ASM mass via increased cell migration.
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The importance of metagenomic surveys to microbial ecology: or why Darwin would have been a metagenomic scientist.
Microb Inform Exp
PUBLISHED: 02-04-2011
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Scientific discovery is incremental. The Merriam-Webster definition of Scientific Method is "principles and procedures for the systematic pursuit of knowledge involving the recognition and formulation of a problem, the collection of data through observation and experiment, and the formulation and testing of hypotheses". Scientists are taught to be excellent observers, as observations create questions, which in turn generate hypotheses. After centuries of science we tend to assume that we have enough observations to drive science, and enable the small steps and giant leaps which lead to theories and subsequent testable hypotheses. One excellent example of this is Charles Darwins Voyage of the Beagle, which was essentially an opportunistic survey of biodiversity. Today, obtaining funding for even small-scale surveys of life on Earth is difficult; but few argue the importance of the theory that was generated by Darwin from his observations made during this epic journey. However, these observations, even combined with the parallel work of Alfred Russell Wallace at around the same time have still not generated an indisputable law of biology. The fact that evolution remains a theory, at least to the general public, suggests that surveys for new data need to be taken to a new level.
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Accelerated dendritic cell differentiation from migrating Ly6C(lo) bone marrow monocytes in early dermal West Nile virus infection.
J. Immunol.
PUBLISHED: 01-19-2011
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No study has investigated the participation of Ly6C(+) monocytes in the earliest phase of skin infection with the mosquito-borne West Nile virus. In a novel murine model mimicking natural dermal infection, CCL2-dependent bone marrow (BM)-derived monocyte migration, differentiation into Ly6C(+) dendritic cells (DC), and accumulation around dermal deposits of infected fibroblasts by day 1 postinfection were associated with increasing numbers of monocyte-derived TNF/inducible NO synthase-producing DC by day 2 postinfection in draining auricular lymph nodes (ALN). Adoptive transfer demonstrated simultaneous migration of bone marrow-derived Ly6C(lo) monocytes to virus-infected dermis and ALN, where they first become Ly6C(hi) DC within 24 h and then Ly6C(lo) DC by 72 h. DC migration from the infected dermis to the ALN derived exclusively from Ly6C(lo) BM monocytes. This demonstrates that Ly6C(hi) and Ly6C(lo) BM-derived monocytes have different fates in vivo and suggests that BM may be a reservoir of preinflammatory monocytes for rapid deployment as inflammatory DC during virus infection.
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Rhinovirus infection induces expression of airway remodelling factors in vitro and in vivo.
Respirology
PUBLISHED: 01-05-2011
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A hallmark of asthma is airway remodelling, which includes increased deposition of extracellular matrix (ECM) protein. Viral infections may promote the development of asthma and are the most common causes of asthma exacerbations. We evaluated whether rhinovirus (RV) infection induces airway remodelling, as assessed by ECM deposition.
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Effect of P2 receptor blockade with pyridoxine on sympathetic response to exercise pressor reflex in humans.
J. Physiol. (Lond.)
PUBLISHED: 11-15-2010
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During exercise, sympathetic nervous system activity increases and this contributes to an increase in blood pressure (i.e. exercise pressor reflex). Although animal studies suggest that purinergic P2 receptors on thin fibre sensory nerves are stimulated and evoke this reflex, human data are lacking. In this study, young healthy volunteers performed fatiguing isometric handgrip before and after a local infusion of pyridoxine (i.e. vitamin B(6)) into the isolated circulation of the human forearm. Pyridoxine is converted into a P2-purinoceptor antagonist. Muscle sympathetic nerve activity and blood pressure responses to fatiguing handgrip and post-exercise circulatory occlusion were significantly less after pyridoxine than they were before. These effects were not observed after infusion of saline. These data suggest that P2 receptors contribute to the exercise pressor reflex in humans.
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Implicit value judgments in the measurement of health inequalities.
Milbank Q
PUBLISHED: 04-10-2010
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Quantitative estimates of the magnitude, direction, and rate of change of health inequalities play a crucial role in creating and assessing policies aimed at eliminating the disproportionate burden of disease in disadvantaged populations. It is generally assumed that the measurement of health inequalities is a value-neutral process, providing objective data that are then interpreted using normative judgments about whether a particular distribution of health is just, fair, or socially acceptable.
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Exposure to low-dose trichloroethylene alters shear stress gene expression and function in the developing chick heart.
Cardiovasc. Toxicol.
PUBLISHED: 02-27-2010
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Trichloroethylene is an organic solvent used as an industrial degreasing agent. Due to its widespread use and volatile nature, TCE is a common environmental contaminant. Trichloroethylene exposure has been implicated in the etiology of heart defects in human populations and animal models. Recent data suggest misregulation of Ca2+ homeostasis in H9c2 cardiomyocyte cell line after TCE exposure. We hypothesized that misregulation of Ca2+ homeostasis alters myocyte function and leads to changes in embryonic blood flow. In turn, changes in cardiac flow are known to cause cardiac malformations. To investigate this hypothesis, we dosed developing chick embryos in ovo with environmentally relevant doses of TCE (8 and 800 ppb). RNA was isolated from control and treated embryos at specific times in development for real-time PCR analysis of blood flow markers. Effects were observed on Endothelin-1 (ET-1), Nitric Oxide Synthase-3 (NOS-3) and Krüppel-like Factor 2 (KLF2) expression relative to TCE exposure and consistent with reduced flow. Further, we measured function in the developing heart after TCE exposure by isolating cardiomyocytes and measuring half-width of contraction and sarcomere lengths. These functional data showed a significant increase in half-width of contraction after TCE exposure. These data suggest that perturbation of cardiac function contributes to the etiology of congenital heart defects in TCE-exposed embryos.
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Rhinovirus-induced exacerbations of asthma: How is the {beta}2-adrenoceptor implicated?
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 09-25-2009
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Rhinovirus (RV) infections are the major cause of asthma exacerbations in children and adults. Under normal circumstances, asthmatic airway obstruction improves spontaneously or characteristically briskly in response to inhaled beta(2)-adrenergic receptor (beta(2)AR) agonists. During virus-associated exacerbations, an impaired response to beta(2)AR agonists is observed; the reason for this is not known. The objective of this study was to determine the effect of RV infection on airway smooth muscle beta(2)AR function. The human cell line Beas-2B and primary human bronchial epithelial cells (HBECs) were infected with RV (multiplicity of infection = 1). After 1 or 5 days for primary and Beas-2B cells, respectively, cell culture supernatants were harvested, UV-irradiated to inactivate RV, and applied to human airway smooth muscle cells for 3 days to assess modifications of beta(2)AR function. RV conditioned medium from Beas-2B and HBECs decreased beta(2)AR agonist-induced cAMP by 50 and 65%, respectively (n = 5; P < 0.05). When cAMP was induced independently of the beta(2)AR using forskolin, no impairment was found. Using flow cytometry, we demonstrated that this decrease was likely the result of beta(2)AR desensitization because membrane but not total cell receptor beta(2)AR was decreased. Pretreatment of HBECs and Beas-2B cells but not human airway smooth muscle cells with the corticosteroids dexamethasone or fluticasone abolished virus-mediated beta(2)AR loss of function. This study shows that epithelial infection with RV induces a decrease of beta(2)AR function on airway smooth muscle cells, potentially explaining the clinical observation of loss of beta(2)AR agonist function during RV-induced asthma exacerbations.
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Truncation of titins elastic PEVK region leads to cardiomyopathy with diastolic dysfunction.
Circ. Res.
PUBLISHED: 08-13-2009
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The giant protein titin plays key roles in myofilament assembly and determines the passive mechanical properties of the sarcomere. The cardiac titin molecule has 2 mayor elastic elements, the N2B and the PEVK region. Both have been suggested to determine the elastic properties of the heart with loss of function data only available for the N2B region.
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Site-specific production of IL-6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis.
J. Immunol.
PUBLISHED: 07-13-2009
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IL-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. To establish the role of site-specific production of IL-6 in autoimmunity, we examined myelin oligodendrocyte glycoprotein immunization-induced EAE in transgenic mice (GFAP-IL6) with IL-6 production restricted to the cerebellum. Myelin oligodendrocyte glycoprotein-immunized (Mi-) GFAP-IL6 mice developed severe ataxia but no physical signs of spinal cord involvement, which was in sharp contrast to Mi-wild type (WT) animals that developed classical EAE with ascending paralysis. Immune pathology and demyelination were nearly absent from the spinal cord, but significantly increased in the cerebellum of Mi-GFAP-IL6 mice. Tissue damage in the cerebellum in the Mi-GFAP-IL6 mice was accompanied by increased total numbers of infiltrating leukocytes and increased proportions of both neutrophils and B-cells. With the exception of IL-17 mRNA, which was elevated in both control immunized and Mi-GFAP-IL6 cerebellum, the level of other cytokine and chemokine mRNAs were comparable with Mi-WT cerebellum whereas significantly higher levels of IFN-gamma and TNF-alpha mRNA were found in Mi-WT spinal cord. Thus, site-specific production of IL-6 in the cerebellum redirects trafficking away from the normally preferred antigenic site the spinal cord and acts as a leukocyte "sink" that markedly enhances the inflammatory cell accumulation and disease. The mechanisms underlying this process likely include the induction of specific chemokines, activation of microglia, and activation and loss of integrity of the blood-brain barrier present in the cerebellum of the GFAP-IL6 mice before the induction of EAE.
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Failure to detect the presence of prions in the uterine and gestational tissues from a Gravida with Creutzfeldt-Jakob disease.
Am. J. Pathol.
PUBLISHED: 04-06-2009
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The vertical transmission of a prion disease from infected mothers to their offspring is believed to be one of the routes for the natural spread of animal prion diseases. Supporting this notion is the observation that prion infectivity occurs in the placenta of infected ewes. Furthermore, the prion protein (PrP), both in its cellular form (PrP(C)) and its pathological isoform (PrP(Sc)), has been observed at the fetal-maternal interface of scrapie-infected sheep. However, whether these features of prion infectivity also hold true for human prion diseases is currently unknown. To begin to address such an important question, we examined PrP in the uterus as well as gestational tissues, including the placenta and amniotic fluid, in a pregnant woman with sporadic Creutzfeldt-Jakob disease (CJD). Although the proteinase K (PK)-resistant prion protein, PrP27-30, was present in the brain tissues of the mother, the PrP detected in the uterus, placenta, and amniotic fluid was sensitive to PK digestion. Unlike PrP(C) in the brain and adjacent cerebrospinal fluid, the predominant PrP species in the reproductive and gestational tissues were N-terminally truncated, similar to urine PrP. Our study did not detect abnormal PrP in the reproductive and gestational tissues in this case of CJD. Nevertheless, examination by a highly sensitive bioassay is ongoing to ascertain possible prion infectivity from CJD in the amniotic fluid.
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Comparative proteomics in the corpus callosal sub-regions of postmortem human brain.
Neurochem. Int.
PUBLISHED: 03-16-2009
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The corpus callosum (CC) is a single anatomical region with homologous cytoarchitecture and divided into four sub-regions such as the rostrum, the genu, the body and the splenium. Neuroimaging analysis revealed that susceptibility to clinical neurological diseases of these sub-regions is variable, indicating biochemical and physiological heterogenecity. To understand the biochemical make up of these regions, we compared the protein expression of these three sub-regional areas [the genu, the body and the splenium (n=9)] through 2D proteomics, which is a high-throughput global protein expression analysis technique. Normative proteomic comparison of gels, and analysis of spectra revealed that 17 (identified as 7 proteins), 35 (identified as 20 proteins) and 39 (identified as 21 proteins) protein spots were differentially expressed in the genu vs. the body, the genu vs. the splenium and the body vs. the splenium, respectively. These results suggest that the sub-regions of the CC differ at the level of protein expression. Identified proteins of the different groups belong to several functional classes such as cytoskeletal, metabolic, signaling, oxidative stress and calcium regulation. Interestingly, oxidative stress defense and glucose metabolic pathways of the splenium are quite different from the genu which might be correlated to region specific vulnerability of neuronal illness. Protein expression maps of these regions can be used as a reference source for future studies to investigate the molecular basis of functional differences and degree of pathogenesis of various neurodegenerative diseases of the CC.
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Spinal P2X receptor modulates muscle pressor reflex via glutamate.
J. Appl. Physiol.
PUBLISHED: 01-08-2009
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Static contraction of skeletal muscle evokes reflex increases in blood pressure and heart rate. Previous studies showed that P2X receptors located at the dorsal horn of the spinal cord play a role in modulating the muscle pressor reflex. P2X stimulation can alter release of the excitatory amino acid, glutamate (Glu). In this report, we tested the hypothesis that stimulation of P2X receptors enhances the concentrations of Glu ([Glu]) in the dorsal horn, and that blocking P2X receptors attenuates contraction-induced Glu increases and the resultant reflex pressor response. Contraction was elicited by electrical stimulation of the L(7) and S(1) ventral roots of 14 cats. Glu samples were collected from microdialysis probes inserted in the L(7) level of the dorsal horn of the spinal cord, and dialysate [Glu] was determined using the HPLC method. First, microdialyzing alpha,beta-methylene ATP (0.4 mM) into the dorsal horn significantly increased [Glu]. In addition, contraction elevated [Glu] from baseline of 536 +/- 53 to 1,179 +/- 192 nM (P < 0.05 vs. baseline), and mean arterial pressure by 39 +/- 8 mmHg in the control experiment. Microdialyzing the P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2,4-disulfonic acid (10 mM) into the dorsal horn attenuated the contraction induced-Glu increase (610 +/- 128 to 759 +/- 147 nM; P > 0.05) and pressor response (16 +/- 3 mmHg, P < 0.05 vs. control). Our findings demonstrate that P2X modulates the cardiovascular responses to static muscle contraction by affecting the release of Glu in the dorsal horn of the spinal cord.
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Inflammatory monocytes and the pathogenesis of viral encephalitis.
J Neuroinflammation
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Monocytes are a heterogeneous population of bone marrow-derived cells that are recruited to sites of infection and inflammation in many models of human diseases, including those of the central nervous system (CNS). Ly6Chi/CCR2(hi) inflammatory monocytes have been identified as the circulating precursors of brain macrophages, dendritic cells and arguably microglia in experimental autoimmune encephalomyelitis; Alzheimers disease; stroke; and more recently in CNS infection caused by Herpes simplex virus, murine hepatitis virus, Theilers murine encephalomyelitis virus, Japanese encephalitis virus and West Nile virus. The precise differentiation pathways and functions of inflammatory monocyte-derived populations in the inflamed CNS remains a contentious issue, especially in regard to the existence of monocyte-derived microglia. Furthermore, the contributions of monocyte-derived subsets to viral clearance and immunopathology are not well-defined. Thus, understanding the pathways through which inflammatory monocytes migrate to the brain and their functional capacity within the CNS is critical to inform future therapeutic strategies. This review discusses some of the key aspects of inflammatory monocyte trafficking to the brain and addresses the role of these cells in viral encephalitis.
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IFN regulatory factor 8 is a key constitutive determinant of the morphological and molecular properties of microglia in the CNS.
PLoS ONE
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IFN regulatory factor (IRF) 8 is a transcription factor that has a key role in the cellular response to IFN-? and is pivotal in myeloid cell differentiation. Whether IRF8 plays a role in the development and function of microglia, the tissue-resident myeloid cells of the brain, is unknown. Here, we show IRF8 is a constitutively produced nuclear factor in microglia, which suggested that IRF8 might also be a key homeostatic transcriptional determinant of the microglial cell phenotype. In support of this, in mice with a targeted disruption of the IRF8 gene, microglia were increased in number and showed gross alterations in morphology and surface area. In situ analysis of some key myeloid markers revealed that IRF8-deficient microglia had significantly reduced levels of Iba1, but increased levels of CD206 (mannose receptor) and F4/80 as well as increased tomato lectin binding. Analysis of microglia ex vivo revealed IRF8-deficient microglia had significantly increased levels of CD45, CD11b and F4/80, but significantly decreased levels of the chemokine receptors CCR2, CCR5 and CX3CR1. The known involvement of some of these molecular markers in membrane dynamics and phagocytosis led us to examine the phagocytic capacity of cultured IRF8-deficient microglia, however, this was found to be similar to wild type microglia. We conclude IRF8 is a constitutively produced nuclear factor in resident microglia of the CNS being a crucial transcriptional determinant of the phenotype of these cells in the healthy brain.
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Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis.
Nat. Biotechnol.
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Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide-co-glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease. These beneficial effects require microparticle uptake by marginal zone macrophages expressing the scavenger receptor MARCO and are mediated in part by the activity of regulatory T cells, abortive T-cell activation and T-cell anergy. Together these data highlight the potential for using microparticles to target natural apoptotic clearance pathways to inactivate pathogenic T cells and halt the disease process in autoimmunity.
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Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages.
J Neuroinflammation
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Infiltration of Ly6C(hi) monocytes from the blood is a hallmark of viral encephalitis. In mice with lethal encephalitis caused by West Nile virus (WNV), an emerging neurotropic flavivirus, inhibition of Ly6C(hi) monocyte trafficking into the brain by anti-very late antigen (VLA)-4 integrin antibody blockade at the time of first weight loss and leukocyte influx resulted in long-term survival of up to 60% of infected mice, with subsequent sterilizing immunity. This treatment had no effect on viral titers but appeared to be due to inhibition of Ly6C(hi) macrophage immigration. Although macrophages isolated from the infected brain induced WNV-specific CD4(+) T-cell proliferation, T cells did not directly contribute to pathology, but are likely to be important in viral control, as antibody-mediated T-cell depletion could not reproduce the therapeutic benefit of anti-VLA-4. Instead, 70% of infiltrating inflammatory monocyte-derived macrophages were found to be making nitric oxide (NO). Furthermore, aminoguanidine-mediated inhibition of induced NO synthase activity in infiltrating macrophages significantly prolonged survival, indicating involvement of NO in the immunopathology. These data show for the first time the therapeutic effects of temporally targeting pathogenic NO-producing macrophages during neurotropic viral encephalitis.
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Aluminum plasmonic nanoantennas.
Nano Lett.
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The use of aluminum for plasmonic nanostructures opens up new possibilities, such as access to short-wavelength regions of the spectrum, complementary metal-oxide-semiconductor (CMOS) compatibility, and the possibility of low-cost, sustainable, mass-producible plasmonic materials. Here we examine the properties of individual Al nanorod antennas with cathodoluminescence (CL). This approach allows us to image the local density of optical states (LDOS) of Al nanorod antennas with a spatial resolution less than 20 nm and to identify the radiative modes of these nanostructures across the visible and into the UV spectral range. The results, which agree well with finite difference time domain (FDTD) simulations, lay the groundwork for precise Al plasmonic nanostructure design for a variety of applications.
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Who cares about health inequalities? Cross-country evidence from the World Health Survey.
Health Policy Plan
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Reduction of health inequalities within and between countries is a global health priority, but little is known about the determinants of popular support for this goal. We used data from the World Health Survey to assess individual preferences for prioritizing reductions in health and health care inequalities. We used descriptive tables and regression analysis to study the determinants of preferences for reducing health inequalities as the primary health system goal. Determinants included individual socio-demographic characteristics (age, sex, urban residence, education, marital status, household income, self-rated health, health care use, satisfaction with health care system) and country-level characteristics [gross domestic product (GDP) per capita, disability-free life expectancy, equality in child mortality, income inequality, health and public health expenditures]. We used logistic regression to assess the likelihood that individuals ranked minimizing inequalities first, and rank-ordered logistic regression to compare the ranking of other priorities against minimizing health inequalities. Individuals tended to prioritize health system goals related to overall improvement (improving population health and health care responsiveness) over those related to equality and fairness (minimizing inequalities in health and responsiveness, and promoting fairness of financial contribution). Individuals in countries with higher GDP per capita, life expectancy, and equality in child mortality were more likely to prioritize minimizing health inequalities.
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Use of relative and absolute effect measures in reporting health inequalities: structured review.
BMJ
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To examine the frequency of reporting of absolute and relative effect measures in health inequalities research.
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Commentary on Biodefence and the production of knowledge: rethinking the problem.
J Med Ethics
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Buchanan and Kelley provide a sophisticated and thoughtful critique of contemporary discussions of biosecurity. They provide sound critiques of American biodefence institutions, and the general sense of imminent threat underlying the rush to fund biodefence. However, the essay consistently misrepresents the breadth and depth of scholarly research on the ethics and politics of biodefence.
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Entry of herpes simplex virus type 1 (HSV-1) into the distal axons of trigeminal neurons favors the onset of nonproductive, silent infection.
PLoS Pathog.
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Following productive, lytic infection in epithelia, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons that is interrupted by episodes of reactivation. In order to better understand what triggers this lytic/latent decision in neurons, we set up an organotypic model based on chicken embryonic trigeminal ganglia explants (TGEs) in a double chamber system. Adding HSV-1 to the ganglion compartment (GC) resulted in a productive infection in the explants. By contrast, selective application of the virus to distal axons led to a largely nonproductive infection that was characterized by the poor expression of lytic genes and the presence of high levels of the 2.0-kb major latency-associated transcript (LAT) RNA. Treatment of the explants with the immediate-early (IE) gene transcriptional inducer hexamethylene bisacetamide, and simultaneous co-infection of the GC with HSV-1, herpes simplex virus type 2 (HSV-2) or pseudorabies virus (PrV) helper virus significantly enhanced the ability of HSV-1 to productively infect sensory neurons upon axonal entry. Helper-virus-induced transactivation of HSV-1 IE gene expression in axonally-infected TGEs in the absence of de novo protein synthesis was dependent on the presence of functional tegument protein VP16 in HSV-1 helper virus particles. After the establishment of a LAT-positive silent infection in TGEs, HSV-1 was refractory to transactivation by superinfection of the GC with HSV-1 but not with HSV-2 and PrV helper virus. In conclusion, the site of entry appears to be a critical determinant in the lytic/latent decision in sensory neurons. HSV-1 entry into distal axons results in an insufficient transactivation of IE gene expression and favors the establishment of a nonproductive, silent infection in trigeminal neurons.
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Microarray analysis of gene expression in West Nile virus-infected human retinal pigment epithelium.
Mol. Vis.
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To identify key genes differentially expressed in the human retinal pigment epithelium (hRPE) following low-level West Nile virus (WNV) infection.
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Mice deficient in STAT1 but not STAT2 or IRF9 develop a lethal CD4+ T-cell-mediated disease following infection with lymphocytic choriomeningitis virus.
J. Virol.
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Interferon (IFN) signaling is crucial for antiviral immunity. While type I IFN signaling is mediated by STAT1, STAT2, and IRF9, type II IFN signaling requires only STAT1. Here, we studied the roles of these signaling factors in the host response to systemic infection with lymphocytic choriomeningitis virus (LCMV). In wild-type (WT) mice and mice lacking either STAT2 or IRF9, LCMV infection was nonlethal, and the virus either was cleared (WT) or established persistence (STAT2 knockout [KO] and IRF9 KO). However, in the case of STAT1 KO mice, LCMV infection was lethal and accompanied by severe multiorgan immune pathology, elevated expression of various cytokine genes in tissues, and cytokines in the serum. This lethal phenotype was unaltered by the coabsence of the gamma interferon (IFN-?) receptor and hence was not dependent on IFN-?. Equally, the disease was not due to a combined defect in type I and type II IFN signaling, as IRF9 KO mice lacking the IFN-? receptor survived infection with LCMV. Clearance of LCMV is mediated normally by CD8(+) T cells. However, the depletion of these cells in LCMV-infected STAT1 KO mice was delayed, but did not prevent, lethality. In contrast, depletion of CD4(+) T cells prevented lethality in LCMV-infected STAT1 KO mice and was associated with a reduction in tissue immune pathology. These studies highlight a fundamental difference in the role of STAT1 versus STAT2 and IRF9. While all three factors are required to limit viral replication and spread, only STAT1 has the unique function of preventing the emergence of a lethal antiviral CD4(+) T-cell response.
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Flavivirus infection induces indoleamine 2,3-dioxygenase in human monocyte-derived macrophages via tumor necrosis factor and NF-?B.
J. Leukoc. Biol.
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Infection with West Nile virus (WNV) via a mosquito bite results in local viral replication in the skin, followed by viremia. Thus, tissue macrophages are ideally located to prevent the dissemination of WNV throughout the host. The current study shows that WNV infection of human monocyte-derived macrophages (MDM) results in increased WNV mRNA, protein, and infectious virions at 24 h p.i. with a decline in titer after 48 h. Concomitant with viral control was the robust induction of indoleamine 2,3-dioxygenase (IDO) and resultant metabolism of L-tryptophan (L-Trp) to kynurenine. In WNV-exposed cultures, IDO protein was induced primarily in noninfected versus viral-infected MDM. Whereas WNV infection increased the production of IFN-?, IFN-?, and TNF, only antibody neutralization of TNF attenuated IDO expression and activity. WNV infection also activated NF-?B, and inhibition of this pathway with BMS-345541 abrogated IDO induction. Similar results were also obtained with MDM infected with the related flavivirus, Japanese encephalitis virus. Whereas IDO-mediated L-Trp metabolism can exhibit antiviral properties, inhibition of IDO activity in MDM with L-1-MT or the addition of excess L-Trp did not affect viral control. However, culturing MDM in L-Trp-deficient medium or overexpression of IDO in cells prior to infection significantly attenuated WNV replication, which was reversed by adding excess L-Trp. Together, these data support that although IDO is not required by MDM for the clearance of established viral infection, the spread of flavivirus infection is limited by IDO expressed in uninfected, neighboring cells.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.