ABSTRACT
Exposure to geogenic (earth-derived) particulate matter (PM) is linked to an increased prevalence of bronchiectasis and other respiratory infections in Australian Indigenous communities. Experimental studies have shown that the concentration of iron in geogenic PM is associated with the magnitude of respiratory health effects, however, the mechanism is unclear. We investigated the effect of geogenic PM and iron oxide on the invasiveness of non-typeable Haemophilus influenzae (NTHi). Peripheral blood mononuclear cell-derived macrophages or epithelial cell lines (A549 & BEAS-2B) were exposed to whole geogenic PM, their primary constituents (haematite, magnetite or silica) or diesel exhaust particles (DEP). The uptake of bacteria was quantified by flow cytometry and whole genome sequencing (WGS) was performed on NTHi strains. Geogenic PM increased the invasiveness of NTHi in bronchial epithelial cells. Of the primary constituents, haematite also increased NTHi invasion with magnetite and silica having significantly less impact. Furthermore, we observed varying levels of invasiveness amongst NTHi isolates. WGS analysis suggested isolates with more genes associated with heme acquisition were more virulent in BEAS-2B cells. The present study suggests that geogenic particles can increase the susceptibility of bronchial epithelial cells to select bacterial pathogens in vitro, a response primarily driven by haematite content in the dust. This demonstrates a potential mechanism linking exposure to iron-laden geogenic PM and high rates of chronic respiratory infections in remote communities in arid environments.
ABSTRACT
A fast and effective one-pot tandem process that generates Heck coupled products from readily available anilines via stable aryl diazonium tosylate salts was developed. The mild and simple procedure involves rapid formation of aryl diazonium salts using a polymer-supported nitrite reagent and p-tosic acid, followed by a base-free Heck-Matsuda coupling with acrylates and styrenes. Using 2-nitroanilines as substrates, the one-pot tandem process was extended for the direct synthesis of 3,4-dihydroquinolin-2-ones. In this case, following diazotization and Heck-Matsuda coupling to give methyl cinnamates, addition of hydrogen and reutilization of the palladium catalyst for reduction of the nitro group and hydrogenation of the alkene resulted in efficient formation of 3,4-dihydroquinolin-2-ones. The synthetic utility of this one-pot, four-stage process was demonstrated with the five-pot synthesis of a quinolinone-based sodium ion channel modulator.
ABSTRACT
Inhalation of particulate matter less than 10 µm in diameter (PM10) has a range of implications for respiratory health. In order to mitigate these effects regulatory bodies have set ambient air quality guidelines based on the known dose-response relationships between PM10 exposure and health outcomes. However, these data are based almost entirely on PM10 from urban regions, which are typically dominated by particulates from combustion sources. In contrast, there are limited data on the respiratory health effects of particles from nonurban regions that often contain a high geogenic (earth derived) component. In this narrative review, we summarize the existing evidence for the respiratory health effects of inhalation of geogenic PM10. We outline the impact of physicochemical properties on the lung response, with a view to identifying gaps in the field.
Subject(s)
Air Pollutants/toxicity , Particulate Matter/toxicity , Respiratory System/drug effects , Air Pollutants/chemistry , Animals , Geography , Humans , Middle East , Military Personnel , Particle Size , Particulate Matter/chemistryABSTRACT
There are many transmembrane receptor-like proteins whose ligands have not been identified. A strategy for finding ligands when little is known about their tissue source is to screen each extracellular protein individually expressed in an array format by using a sensitive functional readout. Taking this approach, we have screened a large collection (3,191 proteins) of extracellular proteins for their ability to activate signaling of an orphan receptor, leukocyte tyrosine kinase (LTK). Only two related secreted factors, FAM150A and FAM150B (family with sequence similarity 150 member A and member B), stimulated LTK phosphorylation. FAM150A binds LTK extracellular domain with high affinity (K(D) = 28 pM). FAM150A stimulates LTK phosphorylation in a ligand-dependent manner. This strategy provides an efficient approach for identifying functional ligands for other orphan receptors.
Subject(s)
Cytokines/metabolism , Proteome/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Signal Transduction/physiology , Cytokines/genetics , Female , HEK293 Cells , Humans , Male , Phosphorylation/physiology , Protein Binding/physiology , Protein Structure, Tertiary , Proteome/genetics , Proteomics , Receptor Protein-Tyrosine Kinases/geneticsABSTRACT
Human agency or the expression of intentionality towards some form of betterment has long occupied human imagination and creativity. The ways in which we express such aspirations are fundamentally informed by our beliefs about the nature of reality, meanings of human well-being and progress, and the ways in which our social locations shape our interests. Within Western health-promoting discourse and practice, such processes have largely been expressed through the construct of empowerment. To date, like health, much empowerment practice has been implicitly rooted in Cartesianism, has tended towards anthropocentrism and in cases where it has engaged with environmental issues, has mirrored environmentalism's focus on externalities and objectivity. These tendencies coupled with the increasing complexity of global, ecological, human well-being issues call empowerment practitioners to integrate new kinds of capacities more suited to addressing the ecological determinants of health. Drawing in part on the author's empowerment research over more than a decade, this article distinguishes between a range of epistemological perspectives underlying contemporary empowerment practices while fore-grounding the concepts of place-based agency and social-ecological resilience. These constructs in turn form the basis for three capacities considered critical for practitioners addressing human-ecological well-being.
Subject(s)
Health Promotion/methods , Power, Psychological , Social Environment , Environmental Health , Health Promotion/standards , Humans , Knowledge , Personal Satisfaction , Population Groups , Sustainable GrowthABSTRACT
Infection by parasitic nematodes is widespread in the developing world causing extensive morbidity and mortality. Furthermore, infection of animals is a global problem, with a substantial impact on food production. Here we identify small molecule inhibitors of a nematode-specific metalloprotease, DPY-31, using both known metalloprotease inhibitors and virtual screening. This strategy successfully identified several µM inhibitors of DPY-31 from both the human filarial nematode Brugia malayi, and the parasitic gastrointestinal nematode of sheep Teladorsagia circumcincta. Further studies using both free living and parasitic nematodes show that these inhibitors elicit the severe body morphology defect 'Dumpy' (Dpy; shorter and fatter), a predominantly non-viable phenotype consistent with mutants lacking the DPY-31 gene. Taken together, these results represent a start point in developing DPY-31 inhibition as a totally novel mechanism for treating infection by parasitic nematodes in humans and animals.
Subject(s)
Helminth Proteins/antagonists & inhibitors , Nematoda/enzymology , Protease Inhibitors/chemistry , Animals , Binding Sites , Brugia malayi/enzymology , Caenorhabditis elegans/enzymology , Caenorhabditis elegans Proteins/antagonists & inhibitors , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Helminth Proteins/metabolism , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/metabolism , Inhibitory Concentration 50 , Metalloendopeptidases/antagonists & inhibitors , Metalloendopeptidases/genetics , Metalloendopeptidases/metabolism , Metalloproteases/antagonists & inhibitors , Metalloproteases/metabolism , Molecular Docking Simulation , Protease Inhibitors/metabolism , Protein Structure, Tertiary , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , SheepABSTRACT
A common evolutionary mechanism in biology to drive function is protein oligomerization. In prokaryotes, the symmetrical assembly of repeating protein units to form homomers is widespread, yet consideration in vitro of whether such assemblies have functional or mechanistic consequences is often overlooked. Dye-decolorizing peroxidases (DyPs) are one such example, where their dimeric α + ß barrel units can form various oligomeric states, but the oligomer influence, if any, on mechanism and function has received little attention. In this work, we have explored the oligomeric state of three DyPs found in Streptomyces lividans, each with very different mechanistic behaviors in their reactions with hydrogen peroxide and organic substrates. Using analytical ultracentrifugation, we reveal that except for one of the A-type DyPs where only a single sedimenting species is detected, oligomer states ranging from homodimers to dodecamers are prevalent in solution. Using cryo-EM on preparations of the B-type DyP, we determined a 3.02 Å resolution structure of a hexamer assembly that corresponds to the dominant oligomeric state in solution as determined by analytical ultracentrifugation. Furthermore, cryo-EM data detected sub-populations of higher-order oligomers, with one of these formed by an arrangement of two B-type DyP hexamers to give a dodecamer assembly. Our solution and structural insights of these oligomer states provide a new framework to consider previous mechanistic studies of these DyP members and are discussed in terms of long-range electron transfer for substrate oxidation and in the "storage" of oxidizable equivalents on the heme until a two-electron donor is available.
Subject(s)
Coloring Agents , Oxidation-Reduction , Peroxidases , Protein Multimerization , Streptomyces lividans , Streptomyces lividans/enzymology , Peroxidases/chemistry , Peroxidases/metabolism , Coloring Agents/chemistry , Coloring Agents/metabolism , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Models, Molecular , Substrate Specificity , Cryoelectron Microscopy , Hydrogen Peroxide/chemistry , Hydrogen Peroxide/metabolismABSTRACT
A considerable bottleneck in serial crystallography at XFEL and synchrotron sources is the efficient production of large quantities of homogenous, well diffracting microcrystals. Efficient high-throughput screening of batch-grown microcrystals and the determination of ground-state structures from different conditions is thus of considerable value in the early stages of a project. Here, a highly sample-efficient methodology to measure serial crystallography data from microcrystals by raster scanning within standard in situ 96-well crystallization plates is described. Structures were determined from very small quantities of microcrystal suspension and the results were compared with those from other sample-delivery methods. The analysis of a two-dimensional batch crystallization screen using this method is also described as a useful guide for further optimization and the selection of appropriate conditions for scaling up microcrystallization.
Subject(s)
Synchrotrons , Crystallography, X-Ray , Crystallization/methods , Data CollectionABSTRACT
Interleukin-34 (IL-34) and colony stimulating factor-1 (CSF-1) both signal through the CSF-1R receptor tyrosine kinase, but they have no sequence homology, and their functions and signaling activities are not identical. We report the crystal structures of mouse IL-34 alone and in complex with the N-terminal three immunoglobulin-like domains (D1-D3) of mouse CSF-1R. IL-34 is structurally related to other helical hematopoietic cytokines, but contains two additional helices integrally associated with the four shared helices. The non-covalently linked IL-34 homodimer recruits two copies of CSF-1R on the sides of the helical bundles, with an overall shape similar to the CSF-1:CSF-1R complex, but the flexible linker between CSF-1R D2 and D3 allows these domains to clamp IL-34 and CSF-1 at different angles. Functional dissection of the IL-34:CSF-1R interface indicates that the hydrophobic interactions, rather than the salt bridge network, dominate the biological activity of IL-34. To degenerately recognize two ligands with completely different surfaces, CSF-1R apparently takes advantage of different subsets of a chemically inert surface that can be tuned to fit different ligand shapes. Differentiated signaling between IL-34 and CSF-1 is likely achieved by the relative thermodynamic independence of IL-34 vs. negative cooperativity of CSF-1 at the receptor-recognition sites, in combination with the difference in hydrophobicity which dictates a more stable IL-34:CSF-1R complex compared to the CSF-1:CSF-1R complex.
Subject(s)
Interleukins/chemistry , Macrophage Colony-Stimulating Factor/chemistry , Receptor, Macrophage Colony-Stimulating Factor/chemistry , Animals , Baculoviridae/genetics , Binding Sites , Crystallography, X-Ray , Gene Expression , Genetic Vectors , Hydrophobic and Hydrophilic Interactions , Interleukins/genetics , Interleukins/metabolism , Kinetics , Ligands , Macrophage Colony-Stimulating Factor/genetics , Macrophage Colony-Stimulating Factor/metabolism , Mice , Models, Molecular , Protein Structure, Secondary , Protein Structure, Tertiary , Receptor, Macrophage Colony-Stimulating Factor/genetics , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sf9 Cells/cytology , Sf9 Cells/metabolism , Signal Transduction , Spodoptera , ThermodynamicsABSTRACT
Innate immune responses to inflammation and infection are complex and represent major challenges for developing much needed new treatments for chronic inflammatory diseases and drug-resistant infections. To be ultimately successful, the immune response must be balanced to allow pathogen clearance without excess tissue damage, processes controlled by pro- and anti-inflammatory signals. The roles of anti-inflammatory signalling in raising an appropriate immune response are underappreciated, representing overlooked potential drug targets. This is especially true in neutrophils, a difficult cell type to study ex vivo owing to a short lifespan, dogmatically seen as being highly pro-inflammatory. Here, we have generated and describe the first zebrafish transgenic line [TgBAC(arg2:eGFP)sh571] that labels expression of the anti-inflammatory gene arginase 2 (arg2) and show that a subpopulation of neutrophils upregulate arginase soon after immune challenge with injury and infection. At wound-healing stages, arg2:GFP is expressed in subsets of neutrophils and macrophages, potentially representing anti-inflammatory, polarised immune cell populations. Our findings identify nuanced responses to immune challenge in vivo, responses that represent new opportunities for therapeutic interventions during inflammation and infection.
Subject(s)
Arginase , Zebrafish , Animals , Zebrafish/metabolism , Arginase/genetics , Arginase/metabolism , Animals, Genetically Modified , Neutrophils , Inflammation , Anti-Inflammatory Agents/metabolismABSTRACT
BACKGROUND: The 2022 outbreak of mpox (formerly known as monkeypox) led to the spread of monkeypox virus (MPXV) in over 110 countries, demanding effective disease management and surveillance. As current diagnostics rely largely on centralised laboratory testing, our objective was to develop a simple rapid point-of-care assay to detect MPXV in clinical samples using isothermal amplification coupled with CRISPR and CRISPR-associated protein (Cas) technology. METHODS: In this proof-of-concept study, we developed a portable isothermal amplification CRISPR-Cas12a-based assay for the detection of MPXV. We designed a panel of 22 primer-guide RNA sets using pangenome and gene-agnostic approaches, and subsequently shortlisted the three sets producing the strongest signals for evaluation of analytical sensitivity and specificity using a fluorescence-based readout. The set displaying 100% specificity and the lowest limit of detection (LOD) was selected for further assay validation using both a fluorescence-based and lateral-flow readout. Assay specificity was confirmed using a panel of viral and bacterial pathogens. Finally, we did a blind concordance study on genomic DNA extracted from 185 clinical samples, comparing assay results with a gold-standard quantitative PCR (qPCR) assay. We identified the optimal time to detection and analysed the performance of the assay relative to qPCR using receiver operating characteristic (ROC) curves. We also assessed the compatibility with lateral-flow strips, both visually and computationally, where strips were interpreted blinded to the fluorescence results on the basis of the presence or absence of test bands. FINDINGS: With an optimal run duration of approximately 45 min from isothermal amplification to CRISPR-assay readout, the MPXV recombinase polymerase amplification CRISPR-Cas12a-based assay with the selected primer-guide set had an LOD of 1 copy per µL and 100% specificity against tested viral pathogens. Blinded concordance testing of 185 clinical samples resulted in 100% sensitivity (95% CI 89·3-100) and 99·3% specificity (95% CI 95·7-100) using the fluorescence readout. For optimal time to detection by fluorescence readout, we estimated the areas under the ROC curve to be 0·98 at 2 min and 0·99 at 4 min. Lateral-flow strips had 100% sensitivity (89·3-100) and 98·6% specificity (94·7-100) with both visual and computational assessment. Overall, lateral-flow results were highly concordant with fluorescence-based readouts (179 of 185 tests, 96·8% concordant), with discrepancies associated with low viral load samples. INTERPRETATION: Our assay for the diagnosis of mpox displayed good performance characteristics compared with qPCR. Although optimisation of the assay will be required before deployment, its usability and versatility present a potential solution to MPXV detection in low-resource and remote settings, as well as a means of community-based, on-site testing. FUNDING: Victorian Medical Research Accelerator Fund and the Australian Government Department of Health.
ABSTRACT
Intracellular infections rely on host cell survival for replication and have evolved several mechanisms to prevent infected cells from dying. Drugs that promote apoptosis, a noninflammatory form of cell death, can dysregulate these survival mechanisms to kill infected cells via a mechanism that resists the evolution of drug resistance. Two such drug classes, known as SMAC mimetics and BH3 mimetics, have shown preclinical efficacy at mediating clearance of liver-stage malaria and chronic infections such as hepatitis-B virus and Mycobacterium tuberculosis. Emerging toxicity and efficacy data have reinforced the broad applicability of these drugs and form the foundations for preclinical and clinical studies into their various usage cases.
Subject(s)
Apoptosis Regulatory Proteins , Apoptosis , Humans , Cell DeathABSTRACT
Nitric oxide (NO) is involved in many biological processes affecting the cardiovascular, nervous and immune systems. Intracellular NO can be monitored using fluorescent probes in combination with fluorescence imaging techniques. Most of the currently available NO fluorescent molecular probes are excited via one-photon excitation using UV or Vis light, which results in poor penetration and high photodamage to living tissues. Here, we report a two-photon fluorescent molecular probe, DANPY-NO, able to detect NO in live cells. The probe consists of an o-phenylenediamine linked to a naphthalimide core; and operates via photoinduced electron transfer. DANPY-NO exhibits good sensitivity (LOD of 77.8 nM) and high selectivity towards NO, and is stable over a broad range of pHs. The probe targeted acidic organelles within macrophages and endothelial cells, and demonstrated enhanced photostability over a commercially available NO probe. DANPY-NO was used to selectively detect endogenous NO in RAW264.7Ï NO- macrophages, THP-1 human leukemic cells, primary mouse (bone marrow-derived) macrophages and endothelial cells. The probe was also able to detect exogenous NO in endothelial cells and distinguish between increasing concentrations of NO. The NO detection was evidenced using confocal laser scanning and two-photon microscopies, and flow cytometry. Further evidence was obtained by recording the changes in the intracellular fluorescence emission spectrum of the probe. Importantly, the probe displayed negligible toxicity to the analysed biological samples. The excellent sensitivity, selectivity, stability and versatility of DANPY-NO confirm its potential for in vitro and in vivo imaging of NO.
Subject(s)
Fluorescent Dyes , Nitric Oxide , Animals , Endothelial Cells/chemistry , HeLa Cells , Humans , Macrophages , Mice , Molecular Probes , PhotonsABSTRACT
Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation; and validate whether 18F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BPTC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5-24.5 µSv/MBq). 18F-LW223 BPTC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm3/mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BPTC analysis. Conclusion:18F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI.
Subject(s)
Macrophages/metabolism , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/immunology , Polymorphism, Single Nucleotide , Positron Emission Tomography Computed Tomography , Receptors, GABA/metabolism , Animals , Fluorine Radioisotopes/analysis , Inflammation/immunology , Macrophages/cytology , Macrophages/immunology , Male , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Radioactive Tracers , Rats, Sprague-Dawley , Receptors, GABA/geneticsABSTRACT
Indigenous peoples have long been successful at adapting to climatic and environmental changes. However, anthropogenic climatic crisis represents an epoch of intensified colonialism which poses particular challenges to Indigenous peoples throughout the world, including those in wealthier 'modern' nation states. Indigenous peoples also possess worldviews and traditional knowledge systems that are critical to climate mitigation and adaptation, yet, paradoxically, these are devalued and marginalized and have yet to be recognized as essential foundations of public health. In this article, we provide an overview of how public health policy and discourse fails Indigenous peoples living in the colonial nation states of Canada and Aotearoa New Zealand. We argue that addressing these systemic failures requires the incorporation of Indigenous knowledges and Indigenous feminist perspectives beyond superficial understandings in public health-related climate change policy and practice, and that systems transformation of this nature will in turn require a radical revision of settler understandings of the determinants of health. Further, public health climate change responses that centre Indigenous knowledges and Indigenous feminist perspectives as presented by Indigenous peoples themselves must underpin from local to global levels.
RéSUMé: Les peuples autochtones ont de tout temps réussi à s'adapter aux changements du climat et de leur environnement. La crise climatique anthropogène constitue toutefois une époque de colonialisme intensifié qui pose des difficultés particulières aux peuples autochtones du monde entier, y compris ceux des États-nations riches et « modernes ¼. Les peuples autochtones possèdent aussi des visions du monde et des systèmes de savoir traditionnels indispensables aux efforts d'atténuation et d'adaptation au changement climatique; paradoxalement, ces visions et systèmes sont dévalués et marginalisés et ne sont pas encore reconnus comme étant des bases essentielles de la santé publique. Dans cet article, nous expliquons en général en quoi les politiques et le discours de la santé publique laissent sur le carreau les peuples autochtones vivant dans les États-nations coloniaux du Canada et d'Aotearoa (la Nouvelle-Zélande). Nous faisons valoir que pour aborder ces échecs systémiques, il faut intégrer les savoirs autochtones et les perspectives féministes autochtones au-delà d'une compréhension superficielle des politiques et des pratiques de santé publique relatives au changement climatique, et qu'une telle transformation des systèmes exigera en retour une révision radicale des savoirs coloniaux sur les déterminants de la santé. Plus encore, les ripostes de la santé publique au changement climatique, que ce soit à l'échelle locale ou mondiale, doivent être centrées sur les savoirs autochtones et les perspectives féministes autochtones tels que présentés par les peuples autochtones eux-mêmes.
Subject(s)
Global Warming , Indigenous Peoples , Public Health , Public Policy , Feminism , Humans , Indigenous Peoples/psychology , KnowledgeABSTRACT
Exposure to geogenic (earth-derived) particulate matter (PM) is linked to severe bacterial infections in Australian Aboriginal communities. Experimental studies have shown that the concentration of iron in geogenic PM is associated with the magnitude of respiratory health effects, however, the mechanism is unclear. We investigated the effect of silica and iron oxide on the inflammatory response and bacterial phagocytosis in macrophages. THP-1 and peripheral blood mononuclear cell-derived macrophages were exposed to iron oxide (haematite or magnetite) or silica PM with or without exposure to lipopolysaccharide. Cytotoxicity and inflammation were assessed by LDH assay and ELISA respectively. The uptake of non-typeable Haemophilus influenzae by macrophages was quantified by flow cytometry. Iron oxide increased IL-8 production while silica also induced significant production of IL-1ß. Both iron oxide and silica enhanced LPS-induced production of TNF-α, IL-1ß, IL-6 and IL-8 in THP-1 cells with most of these responses replicated in PBMCs. While silica had no effect on NTHi phagocytosis, iron oxide significantly impaired this response. These data suggest that geogenic particles, particularly iron oxide PM, cause inflammatory cytokine production in macrophages and impair bacterial phagocytosis. These responses do not appear to be linked. This provides a possible mechanism for the link between exposure to these particles and severe bacterial infection.
Subject(s)
Ferric Compounds/pharmacology , Leukocytes, Mononuclear/drug effects , Lipopolysaccharides , Macrophages/drug effects , Phagocytosis , Australia , Cytokines/metabolism , Haemophilus influenzae , Humans , Lipopolysaccharides/toxicity , Silicon Dioxide/pharmacology , THP-1 CellsABSTRACT
Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.
Subject(s)
Adipocytes, Brown/metabolism , Adipogenesis , Fibroblast Growth Factor 6/metabolism , Fibroblast Growth Factor 9/metabolism , Obesity/metabolism , Uncoupling Protein 1/metabolism , Adipocytes, Brown/cytology , Adipose Tissue, Brown/cytology , Adipose Tissue, Brown/metabolism , Animals , Fibroblast Growth Factor 6/genetics , Fibroblast Growth Factor 9/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Obesity/genetics , Obesity/physiopathology , Thermogenesis , Uncoupling Protein 1/geneticsABSTRACT
In the crystal of the title mol-ecular salt (systematic name: 2-acetyl-pyridinium 2,5-dibromo-4-hydr-oxy-3,6-dioxocyclo-hexa-1,4-dienolate), C(7)H(8)NO(+)·C(6)HBr(2)O(4) (-), centrosymmetric rings consisting of two cations and two anions are formed, with the components linked by alternating O-Hâ¯O and N-Hâ¯O hydrogen bonds. Short Oâ¯Br contacts [3.243â (2) and 3.359â (2)â Å] may help to consolidate the packing.
ABSTRACT
As a signatory to Convention on the Rights of People with Disabilities, Aotearoa New Zealand aims to be a "non-disabling society-a place where disabled people have an equal opportunity to achieve their goals and aspirations". Yet many adult New Zealanders with severe-to-profound hearing loss (SPHL) due to sensorineural deterioration over time are being denied timely access to publicly funded cochlear implants. This presents a serious inequity in Aotearoa New Zealand's health system and contravenes disability and human rights principles. For Maori affected by SPHL, this brings additional challenges along with broader impacts on Maori health and development. These issues are investigated through a self-case study together with a review of relevant evidence-based research and public policy.