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Mediators of Inflammation
Volume 2012, Article ID 920517, 10 pages
Pentraxin 3(PTX 3): An Endogenous Modulator of the Inflammatory Response
1Department of Cardiac Surgery, University Hospital and Medical School of Hradec Kralove, Charles University in Prague, 12843 Prague, Czech Republic
2Department of Clinical Immunology and Allergology, University Hospital and Medical School of Hradec Kralove, Charles University in Prague, 12843 Prague, Czech Republic
Received 4 December 2011; Revised 30 January 2012; Accepted 1 February 2012
Academic Editor: François Mach
Copyright © 2012 P. Kunes et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Inflammatory or anti-inflammatory? That is the question as far as the acute-phase response and its mediators, the pentraxins, are concerned. Only some ten years ago, the classical or short pentraxin C-reactive protein and the newly discovered long pentraxin PTX3 were considered to exert most of the detrimental effects of acute inflammation, whether microbial or sterile in origin. However, accumulating evidence suggests an at least dichotomous, context-dependent outcome attributable to the pentraxins, if not a straightforward anti-inflammatory nature of the acute-phase response. This paper is focused on the inherent effects of pentraxin 3 in inflammatory responses, mainly in coronary artery disease and in Aspergillus fumigatus infection. Both are examples of inflammatory reactions in which PTX3 is substantially involved; the former sterile, the latter infectious in origin. Apart from different inducing noxae, similarities in the pathogenesis of the two are striking. All the same, the introductory question still persists: is the ultimate impact of PTX3 in these conditions inflammatory or anti-inflammatory, paradoxical as the latter might appear? We try to provide an answer such as it emerges in the light of recent findings.
1. Danger Recognition
The innate immune system provides the first line of defense against microorganisms with which humans are daily contacted. The encounter with the microbial world occurs either on the body's external surface, that is, on the skin, or on its internal (mucosal) surfaces in the airways and in the gastrointestinal tract. The vast majority of these steady-contact microbes are not inherently pathogenic. Nevertheless, their eventual threat to the host may vary considerably according to both external/environmental and to internal conditions, the latter being reflected by the ability of the host to mount an appropriate immune response. Whenever needed, this response must go on to involve the adaptive immune reaction(s). Basically, the same holds true for virtually pathogenic microorganisms. An infection may be brought right under control if confronted with an immunologically competent host. Actually, the net result of pathogen-host interaction, that is, whether health is maintained or disease develops, relies on the balance between pathogen virulence and the capacity of the individual immune response. The innate and adaptive immune reactions form a continuum of closely interrelated steps with innumerable positive and negative feedback loops. Therefore, they should be viewed as two sides of the same coin [1].
To initiate a defense reaction, first of all, a microorganism must be sensed and recognized by the immune system as potentially harmful. It has been established that microorganisms are not recognized in their individual complexity. Instead, several sets of highly conserved molecular moieties which are shared by large groups of microorganisms are implicated in the process of being recognized. These molecular motifs, collectively referred to as alarmins or pathogen-associated molecular patterns (PAMPs), are committed to elicit a danger signal within the immune system. Importantly, closely resembling or even identical molecular structures are present in the host's own cells. Under normal conditions, these molecules are well hidden inside the cellular cytoplasm, far beyond the reach of the recognition machinery. In cells undergoing apoptotic or necrotic death, the hallmark of sepsis or ischemia-reperfusion injury, PAMPs/alarmins are promptly exposed on the surface membrane of the host's cells or even released into the extracellular space [2, 3]. Another way to exhibit own PAMPs/alarmins, albeit in a slow, gradual process, occurs in low-grade inflammation. Examples thereof are atherogenesis or rheumatoid arthritis. Inflammatory diseases which develop in the absence of microorganisms are called sterile inflammation [4].
The constituents of the immune system which are involved in the process of recognizing PAMPs, either of microbial origin in bacteremia/sepsis or modified self-structures in sterile inflammation, are represented by germ line-encoded receptors known as pattern recognition molecules (PRMs). The occurrence of PRMs is not confined to canonical components of the immune system, but other cells are also involved. From the viewpoint of cardiology/cardiac surgery, endothelial cells play a prominent role [5].
Within the human body, pattern recognition molecules/receptors are present either as cell-associated- or as fluid-phase molecules. The former are localized in most tissues, whereas the latter are distributed in the liquid compartment, that is, mainly, but not exclusively, in the blood. Cell-associated receptors are made up by endocytic/scavenger receptors, signalling receptors (e.g., toll-like receptors), and nucleotide-binding oligomerization domain- (NOD-)like receptors [6]. The fluid-phase molecules represent evolutionary ancestors of antigen-specific antibodies. This heterogeneous group of molecules consists of three clearly defined subgroups, that is, the collectins, the ficolins, and the pentraxins. All of them are implicated in complement activation, pathogen opsonisation, and/or self versus modified-self versus non-self discrimination [7].
2. A Brief Glance at the Pentraxin Superfamily
The pentraxins form a superfamily of multifunctional proteins which have been conserved in phylogeny from arachnids to mammals. The pentraxin superfamily is distinguished by the presence in their C(carboxy)-terminal region of a ~200 amino acid domain containing a highly conserved motif of 8-amino-acid sequence, which has been named the pentraxin signature (HxCxS/TWxS, where x is any amino acid). Based on the primary structure of the protomer, the pentraxins branch off into two groups: the short constituents and their long counterparts [8].
Short pentraxins are about 25-kDa proteins sharing a common structural organization of five or ten subunits that are assembled in pentameric radial symmetry. The classical short pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are acute-phase proteins in humans and in mice, respectively. They are manufactured in the liver under the guidance of inflammatory cytokines, most prominently of interleukin (IL)-6 and, to a lesser degree, of IL-1β. CRP is the major acute-phase reactant in humans. Its levels are scarcely detectable in plasma of healthy persons, in whom CRP concentrations do not exceed 3 mg/L (3 μg/mL). However, CRP plasma concentrations increase as much as 1000-fold under inflammatory conditions, irrespective whether of bacterial (sepsis) or sterile (sepsis-like) origin. Classically, the latter develops in patients after trauma and surgical operations or in patients with acute coronary syndromes (unstable angina pectoris/acute myocardial infarction). CRP and SAP bind their respective ligands in a calcium-dependent manner. Both of them play important roles in innate resistance to microbes and in scavenging pathogenic cellular debris including extracellular matrix components [9]. Pentraxin 3(PTX3) was identified in the early 1990s in human endothelial cells and fibroblasts as a TNF-α- or IL-1β-inducible mRNA and protein, respectively. IL-6 does not deal with PTX3 production. Despite manifest similarities of action, PTX3 differs from its short associates in many basic aspects, such as gene organization, chromosomal localization, cellular sources, inducing stimuli and the recognized ligands [10].
3. Genetic Aspects of Pentraxin 3
The human ptx3 gene is localized on the chromosome 3q band 25. It is composed of three exons, the first two of which encode for the signal peptide and the N-terminal domain (amino acids 18–179), respectively. The third exon encodes for the C-terminal domain featuring the pentraxin signature (amino acids 179–381) [11]. Immature myeloid dendritic cells were supposed to be the prevailing cellular population capable to produce PTX3. However, stimulus-induced PTX3 has been detected in other cellular populations, such as the monocytes/macrophages, smooth muscle cells, kidney epithelial cells, synovial cells, chondrocytes, adipocytes, alveolar epithelial cells, glial cells, fibroblasts, and, of course, in endothelial cells [12]. PTX3 promoters contain enhancer-binding elements which, during proteosynthesis, fine-tune final impact of PTX3 on its target structures. The most prominent ones are activator protein-1 (AP-1), nuclear factor-kappa B (NF-κB), and selective promoter factor 1 (SP1) [13]. Briefly, AP-1 enhances basal transcription of PTX3, whereas the NF-κB binding site is operative in the response to inflammatory cytokines TNF-α and/or IL-1β. Tissue-specifically, the above-mentioned transcription factors are complemented, in their proteosynthesis-modulating activities, by enzymatic biochemical pathways. In lung epithelial cells challenging acute inflammation, PTX3 mRNA as such is induced by TNF-α; nevertheless, PTX3 protein generation itself does not require consequent NF-κB transcription. Instead, PTX3 is manufactured by way of the c-Jun N-terminal kinase pathway [14]. In endothelial cells, expression of PTX3 is readily induced by TNF-α and IL-1β. Thereafter, an acute cellular alteration sets in, in which the endothelial cell is converted from a quiescent, anti-inflammatory phenotype, to a procoagulant and proinflammatory cellular surface. This is the case in sepsis/infection or in acute myocardial infarction. On the other hand, endothelial cells are implicated in low-grade sterile inflammation that underlies atherosclerosis and small vessel vasculitides. A counter-regulatory pathway which abrogates unwanted inflammation is carried out by high-density lipoprotein 3 (HDL3) subfraction. This HDL3-controled PTX3 production evades classical regulatory mechanisms in that it relies on the activation of the PI3K/Akt pathway via G-coupled lysosphingolipid receptors. The lysosphingolipid receptor S1P, which is the one responsible for this alternative PTX3 synthesis, is a protein particle carried by HDL3. In human endothelial cells, therefore, PTX3 accomplishes dual outcome according to the respective activators: (i) an inflammatory effect induced by TNF-α and/or IL-1β or (ii) an anti-inflammatory effect induced by S1P/HDL3. The latter is further translated into increased NO-dependent vasorelaxation, endothelial cell antiapoptotic effects, and increased TGF-β expression with ensuing atheroprotective modulation [15]. PTX3 generation is also regulated in a cell-dependent manner by glucocorticoid hormones (GHs). GHs support the production of PTX3 in fibroblasts and endothelial cells, whereas they suppress PTX3 production by haematopoietic cells (dendritic cells and macrophages). Accordingly, intravenous administration of a glucocorticoid hormone increases blood levels of PTX3 [16].
4. Pentraxin 3 Storage in Neutrophils
Apart from the generation of PTX3 in a response to inflammatory stimuli, there is also a constitutive, ready-made form of PTX3 which is stored in specific (lactoferrin+) granules of neutrophils. After these cells have been activated by appropriate stimuli, this preformed amount of PTX3 is released into the extracellular space. This is a virtually mature, that is, glycosylated form of monomeric PTX3 which, once occurring extracellularly, assembles into multimers of five subunits. The PTX3 glycosidic moiety presents a complex of bi-, tri-, and tetra-antennary sialylated structures, the relative number of which undergoes changes reflecting the inflammatory conditions in which actual PTX3 protein has been generated. Glycosylation of PTX3 seemingly functions as a fine-tuning mechanism of the mature protein. Thus, neutrophils represent a ready-to-use reservoir of PTX3 guaranteeing its early release and early activity in acute inflammation [17]. Under normal steady-state conditions, circulating neutrophils exhibit a short half-life terminated by apoptotic death, which serves to protect the host from any undue damage inflicted by these cells. Whenever inflammation is evoked, those stimuli which account for early PTX3 release delay concomitantly neutrophil apoptotic death. This is a natural feedback mechanism maintaining neutrophil numbers within required limits; otherwise, the host would incur premature neutrophil exhaustion leading to attenuation of inflammation. Delayed neutrophil apoptosis is not a selective mechanism. Prolonged neutrophil life-span is needed to support the host protection against infection/sepsis. However, the same scenario, albeit occurring in a slow step-by-step manner, is set in motion in chronic sterile inflammation in which increased numbers of activated neutrophils are harmful to the host. Atherosclerosis may serve as an example thereof, although participation of neutrophils in this process was long underestimated [18].
Upon inflammatory activation, neutrophils release about 25% of their actual PTX3 content. Part of the extruded protein remains associated with the parent cell by way of neutrophil extracellular traps (NETs). This is a chromatin material assembled with nuclear proteins which has been set free concomitantly with PTX. Localization of PTX3 in neutrophil extracellular traps contributes to the generation of an antimicrobial microenvironment which augments local capacity to trap and kill microbes. Given the abundance of neutrophils both in the circulation and in the inflammatory foci, these cells whose life-span has been prolonged into the bargain constitute the main source of PTX3 right after the onset of infection or in acute sterile inflammation, such as myocardial infarction. Neutrophil-released PTX3 is functionally competent well before de novo synthesis by other cells delivers supplemental amounts of the protein. At the same time, neutrophil-derived PTX3 accounts for another feedback mechanism which restricts excess transmigration of activated neutrophils into the host's tissues, thus dampening unwanted dissemination of inflammatory reactions [19].
5. Regulation of Pentraxin 3 Production
Activation stimuli which control PTX3 synthesis and release can be enumerated as follows: (i) proinflammatory cytokines (IL-1β, TNF-α), (ii) TLR agonists, namely lipopolysaccharide (LPS), (iii) distinct microbial moieties (OmpA, lipoarabinomannans), and/or (iv) some intact microorganisms. Taking into account the complexity of the inflammatory/immune reactions, more than one stimulus is usually employed to set off PTX3 production. To initiate the immune response, cell-expressed receptors tightly cooperate with their fluid-phase counterparts after they have recognized hostile microorganisms (non-self) via the latter's PAMPs. Essentially, the same scenario proceeds in cases of sterile inflammation, after the recognition machinery has discriminated own modified or damaged cell structures (altered self) [20]. To give an example, macrophage scavenger receptor CD36 mediates binding and internalization of Gram-positive bacteria by cooperating with toll-like receptors TLR2 and TLR6, thereafter initiating production of proinflammatory cytokines TNF-α, IL-1β, IFN-γ, and many others. Concurrently, production of both short and long pentraxins CRP and PTX3 by their paternal cells may be started off. In contrast to the current paradigm which claims that cytokines considered proinflammatory should be activated to start the inflammatory/innate immunity response, IFN-γ downregulates PTX3 production in dendritic cells and in monocyte-macrophage cell lines. To achieve this, IFN-γ decreases PTX3 mRNA transcription and reduces PTX3 transcript stability, respectively [21]. On top of it, LPS-induced PTX3 expression is downregulated by (i) interleukin-4, (ii) 1α,25-dihydroxivitamin D3, and (iii) prostaglandin E2 [22]. Additionally, PTX3 by itself does not bind to (i) lipopolysaccharide (LPS), (ii) lipoteichoic acid (LTA), (iii) enterotoxins A, and B, (iv) exotoxin A and (v) N-acethylmuramyl-L-alanyl-D-isoglutamine (MDP). Interleukin-(IL-)10, a most prominent anti-inflammatory cytokine, enhances LPS-induced PTX3 production, however, paradoxically it might appear. Due to the impact of IL-10 on dampening inflammation and supporting wound healing, this fact implies that PTX3/IL-10 would play an imortant role in tissue repair [23].
6. Pentraxin 3 in Cardiovascular Diseases
Important pieces of knowledge regarding PTX3 behavior in cardiovascular diseases, such as atherosclerosis and acute myocardial infarction (AMI), have been gained in the last ten years. As early as in 2000, Peri and coworkers published in Circulation their results from a cohort of 37 patients who had presented with an AMI. The authors showed that in these patients, plasma levels of PTX3 peaked as early as ~6 hours after the onset of chest pain. Thus, maximal concentration of PTX3 was available much earlier than that of CRP which is achieved after ~48 hours. In AMI patients, individual levels of PTX3 were attained independently of the extent of myocardial necrosis or incident heart failure assessed by the Killip class [24]. Four years later, these authors extended their original findings by adding that in AMI patients, PTX3 supplied the most powerful information regarding three-month mortality after the index event. In their study, prognostic value of PTX3 was superior to that provided by CRP, CK, TnT, and NT-proBNP [25]. Additional studies introduced PTX3 as a prognostic biomarker in heart failure, both acute and chronic, which was unrelated to an AMI [26, 27]. In the cardiovascular health study, PTX3 has been established to associate with the incidence of CAD and all-cause mortality in CAD patients, independently of CRP and other classical risk factors [28]. In our own study dealing with plasma PTX3 changes in patients undergoing coronary artery bypass grafting, we expectedly documented hundred-fold elevations of CRP in all patients, none of whom suffered any peri- or postoperative complication. However, PTX3 did not exceed the level of 2 ng/mL in any blood sample collected during or up to the 7th day after the operation, this respective value has been set as normal for healthy humans [29]. Studies examining the metabolic syndrome, a prominent risk factor of CAD, do also point out to discordant comportment of CRP and PTX3. Whereas CRP appears to correlate positively with (i) body weight, (ii) body-mass index, (iii) waist circumference, (iv) fasting plasma glucose, and (v) plasma IL-6 levels and negatively with (i) HDL cholesterol and (ii) adiponectin, PTX3 displays the opposite trends. It can be soundly assumed that the functions of PTX3 and CRP complement or even overlap in some situations, wheres in others they diverge substantially. There are even first hints that PTX3 might play an as yet unrecognized protective role in atherosclerosis and its complications [30].
7. Pentraxin 3 in Atherosclerosis
Studies examining PTX3 in the process of atherogenesis found this long pentraxin to be expressed in human vascular smooth muscle cells via atherogenic lipoproteins [31], to up-regulate tissue factor expression both in human endothelial cells [32] and in activated monocytes [33], and to occur extensively in advanced atherosclerotic plaques. Therein, the source of PTX3 is not confined to macrophages and surviving endothelial cells [34], but, importantly, PTX3 is also present in infiltrating neutrophils [35], a cell population increasingly recognized as being active in the initial phase of the disease as well as in its complications [36, 37]. Clinically, PTX3 has been found to operate actively in unstable angina pectoris [38, 39] and in restenosis after coronary artery stent introduction; however, without identifying its source(s) in these conditions [40]. Furthermore, PTX3 displays a predilection to segments of vascular or synovial inflammation in rheumatic diseases, the pathogenesis of which is supposed to have much in common with that of atherosclerosis [41]. As it is, the inaugural question stands out with an intriguing acuity: is pentraxin 3 an inflammatory/harmful or an anti-inflammatory/benefitial mediator?
This question has been partly resolved with the accession of genetically modified mice in whom the PTX3 gene has been silenced (ptx3−/− mice). These animals do not produce any traces of PTX3 protein. When cross-bred with apolipoprotein E gene-deficient (apoe−/−) mice, which is a murine phenotype closely recapitulating the development of human atherosclerosis, mouse strains which result from these combinations (PTX3+/+ or PTX3+/− ApoE−/− versus PTX3−/− ApoE−/−) yielded exciting insights into the involvement of PTX3 in atherogenesis. During the course of aging, PTX3−/− apoE−/− mice develop, in line with expectations, increasing atherosclerosis as a function of time. When fed Western-type diet, these mice display an even increased extent of atherosclerosis. In both settings, that is, normal chow versus Western-diet-fed mice, PTX3 amounts correlated positively with the atherosclerotic burden. By contrast, in PTX3+/+ apoE−/− double knockout mice, the atherosclerotic affliction is unexpectedly enhanced instead of being diminished, which should have been the case if PTX3 was an unequivocal atherogenic mediator. Further studies specified that in atherosclerosis-prone mice, total absence of PTX3 was pronounced in the vascular wall by increased upregulation of (i) proinflammatory mediators such as the chemokines (e.g., CCL2, CCL3, CCL5, CCL7, CCL8) or cytokines (e.g., IL-4, IL-6, TNF-α), (ii) transcription factors such as NF-κB and the related protein Irak1, Fos, Jun, GATA3, GATA4, Egr2, Egr3, (iii) key mediators of the inflammatory response (e.g., TLR-2, TLR-4), and/or (iv) adhesion molecules responsible for the onset of endothelial dysfunction: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (E-selectin), platelet/endothelial cell adhesion molecule (PECAM) [42].
8. Pentraxin 3 in Myocardial Infarction and in Ischemia/Reperfusion Injury
Alberto Mantovani's team furthermore evidenced that in genetically modified mice, PTX3 plays a protective role in acute myocardial infarction, notably in the reperfusion phase. It must be pointed out here that PTX3 is not expressed in the heart under resting conditions, either murine or human. During reperfusion of a previously ischemic myocardium (or, practically, any tissue), an inflammatory response is elicited by explosive production of reactive oxygen species. In the course of reperfusion, an injury develops which is characterized by leukocyte activation and recruitment thereof into the reperfused area; by endothelial dysfunction which paves the way to these cells'apoptotic or necrotic death and/or by cardiomyocyte cell death which occurs as a result of blood flow defects (the "no-reflow" phenomenon). In a model of coronary artery ligation/reperfusion, PTX3−/− mice exhibit more extensive myocardial damage compared to their wild-type littermates. Specifically, reperfusion injury is manifest as (i) increased activated neutrophil and monocyte/macrophage infiltration to the damaged tissue, (ii) decreased number of tissue capillaries including extension of the no-reflow area by endothelial swelling which results in an obstruction of the remaining vessels, and/or (iii) increased number of apoptotic cardiomyocytes caused either by microcirculatory drop-outs, or inflicted to the cardiomyocytes by activated complement. Conversely, administration of exogenous PTX3 to PTX3-deficient mice dampens this injury down to the level experienced by their wild-type littermates. Administration of surplus PTX3 protein seems to confer a supplemental protection not only to the deficient, but also to normal, that is, PTX3+/+ mice [43]. As far as humans are concerned, the situation requires much of further research.
9. Interaction of Pentraxin 3 with Platelets in Acute Myocardial Infarction
Activated platelets cause much of tissue damage in myocardial infarction. Hence, they are the predominant target cells of PTX3. Upon extrusion into the extracellular space, neutrophil-originating PTX3 binds to adjacent platelets which, thereupon, lose much of their robust inflammatory armamentarium. PTX3-stained platelets are thereafter resistant to the formation of platelet-platelet homoaggregates or to platelet-neutrophil or platelet-monocyte heteroaggregates. Furthermore, PTX3 broadly impacts the adhesion molecule P-selectin, which is known to play distinct roles in atherogenesis. PTX3 brings about downregulation of P-selectin-dependent neutrophil recruitment to inflammatory sites and of P-selectin-induced cellular heteroaggregate formation. Hence, decreased numbers of microaggregates are present that would impair blood flow in the microcirculation, not to speak of their additional noxious potential. In acute coronary syndromes, the overall procoagulant state is increased, including excess tissue factor formation by different cell types which makes the blood more "sticky" [44].
Intervention of either endogenous or exogenous PTX3 mitigates the development of the "no-reflow" fenomenon, that is, sustained tissue hypoxia/anoxia despite successful recanalization of large arteries. The jeopardized tissue is imbibed, irrespective of its extent, by a dense infiltrate which is composed largely of granulocytes and macrophages. The same applies to the early necrotic scar before its fibrotic transformation. PTX3 can be detected in most of the infiltrating macrophages and remaining endothelial cells, whereas neutrophils are scarcely found by this time point. If so, a few granulocytes are localized mainly in the center of the lesion, whereas in the outer parts, PTX3 is found only extracellularly. Cardiomyocytes are constantly devoid of PTX3 [45]. On the subcellular level, activities of PTX3 impact the transcription factor NF-κB and its modifying effects on proteosynthesis, since the beneficial outcome is lost in IL-1RI- or MyD88-deficient mice. MyD88 is a cellular adaptor protein downstream of the receptors for TLR and IL-1R. MyD88- or IL-1R-deficient mice are unable to upregulate PTX3 expression and in cases of acute coronary events, these artificial animals behave like those who are entirely lacking the long pentraxin (PTX3-deficient or PTX3−/− mice). Thus, the IL-1R-MyD88 pathway plays a dominant role in ptx3 mRNA induction in heart ischemia. In MyD88- or IL-1R-deficient mice, ample PTX3 protein may be available, but PTX3-borne signal cannot be transmitted from the surface membrane of the target cell to its nucleus where proteosynthesis controled by NF-κB takes place, including that which should supply, among other mediators, more amounts of PTX3 protein [46].
In vitro, preincubation of apoptotic cells with PTX3 enhances complement factor C1q binding and factor C3 deposition on the cellular surface, thus mimicking participation of PTX3 in complement-mediated clearance of apoptotic cells. The in vivo activity of PTX3, however, is dichotomous, depending upon whether complement has been activated systemically in circulating blood or locally in the inflammatory focus. Furthermore, PTX3 binds to late apoptotic neutrophils and inhibits their phagocytosis by monocyte-derived macrophages. Consequently, PTX3−/− mice display increased C3 deposition in their ischemic myocardium, whereas exogenous PTX3 reduces in them complement activation, provided, of course, that the IL-1R-MyD88 pathway is intact. In vitro, inhibition of complement by fluid-phase PTX3 occurs at concentrations in the same range as those achieved in PTX3−/− mice 24 hours after myocardial reperfusion. Therefore, it can be expected that PTX3 protective activities in later phases of an AMI result from its impact on the complement cascade, which accounts for the salvage of apoptosis-destined, but still viable cells [47].
10. Pentraxin 3 Interaction with the Complement System
PTX3 is composed of a unique N-terminal region coupled to a C-terminal domain, which is homologous to the short pentraxins CRP and SAP. The N-terminal region of PTX3 is unrelated to any protein structure known so far. Studies carried out with recombinant preparations of the N- and C-terminal domains of PTX3, respectively, indicate that the N-terminal region binds ligands such as (i) fibroblast growth factor-2 (FGF2), (ii) inter-α-inhibitor, and/or (iii) conidia of A. fumigatus; whereas the pentraxin-like C-terminal domain of PTX3 interacts with the complement factor C1q and the adhesion molecule P-selectin. On the other hand, both the N- and the C-terminal domains have been implicated in the interaction with the complement factor H [48].
The impact of PTX3 on complement activation is a complex issue. PTX3 binds C1q, the first component of the classical complement cascade, by interacting with the C1q globular head (gC1q) and, in particular with charged residues on the apex part of the molecule which encompass all three C1q chains (i.e., gC1qA, gC1qB, and gC1qC) [49]. PTX3 binds to immobilized C1q, such as is aggregated on the surface of bacterial walls. Interaction of PTX3 with surface-bound C1q leads to the activation of the classical pathway, as can be assessed by the deposition of C3 and C4 fragments on the target cells. PTX3 itself, however, does not interact either with C3 or with C4. In contrast, the presence of PTX3 in circulating blood leads to a dose-dependent inhibition of C1q hemolytic activity, an event in which PTX3 limits C1q binding to antibody-sensitized erythrocytes. Hence, binding of fluid-phase PTX3 to free C1q results in the inhibition of the classical cascade of complement. As it is, PTX3 exerts a dual role on the classical pathway of complement: it supports clearance of corpuscular material that binds PTX3, such as microbes or apoptotic cells, while it restricts unwanted complement activation in circulating blood [50].
The short pentraxin CRP, in addition to the classical pathway, modulates the alternative pathway of complement via interaction with factor H, the main soluble regulator of the alternative pathway. PTX3 can also interact with factor H, thus leading to increased factor H and factor iC3b deposition on apoptotic cells. Factor iC3b is the prevalent opsonin generated during complement activation, which performs an important activity in the process of complement-mediated phagocytosis. The net result of PTX3 impact on the alternative pathway of complement is mirrored by increased factor H deposition on PTX3-coated surfaces, that is, activation of complement by the alternative pathway in response to appropriate stimuli is increased. At the same time, however, exaggerated complement activation by the alternative pathway, which is active even under steady-state conditions to guarantee an immediate-early weapon in cases of sudden bacterial intrusion and which might, in a pathogen-free environment, inflict an erroneous damage to the host, is being held under control [51].
PTX3 interacts also with components of the lectin pathway. The mannose binding lectin (MBL) binds PTX3 via its collagen-like domain. MBL/PTX3 complexes recruit C1q and elicit C3 and C4 deposition on target cell surfaces, such as those of Candida albicans. Phagocytosis thereof is mightily enhanced. Furthermore, pentraxin 3 interacts with another fluid-phase PRM, namely, L-Ficolin (alternatively known as ficolin-2). Of note, ficolin-2 has been shown to bind conidia of Aspergillus fumigatus. This ficolin 2-A.fumigatus interaction is supported by PTX3 and conversely, PTX3-A.fumigatus binding is supported by ficolin-2. PTX3 also promotes ficolin-2-induced complement deposition on the surface of A. fumigatus, thus aiding the host to combat the infection [52]. Recently, an interaction between M-ficolin (ficolin-1) and PTX3 has been described in which immobilized PTX3 triggers M-ficolin- induced activation of the lectin complement pathway [53].
11. Pentraxin 3 Interaction with Microbial Moieties
Opsonization of target cells (invading pathogens or altered self structures) results in (i) facilitated pathogen recognition (and increased phagocytosis and killing) and in (ii) innate immune cell activation (and increased inflammatory cytokine and nitric oxide production). Moreover, opsonization by PTX3 is evidently linked to the activation of an appropriate adaptive immune response (i.e., dendritic cell maturation and polarization). PTX3 opsonizes manifold pathogens or pathogen-derived ligands, most importantly zymosan, Paracoccidioides brasiliensis or conidia of Aspergillus fumigatus [54]. Other interactions concern Gram-positive and Gram-negative bacteria, namely, Staphyloccocus aureus, Pseudomonas aeruginosa, Salmonella typhimurium, Streptococcus pneumoniae, and Neisseria meningitidis. Even viruses are affected, namely, human and murine cytomegalovirus (CMV) or H3N2 influenza virus.
PTX3 binds the outer membrane protein A from Klebsiella pneumoniae (KpOmpA). OmpA, an archetypical pathogen-associated molecular pattern, is a prominent membrane component of Gram-negative bacteria, which has been conserved in phylogeny among the enterobacteriaceae family. As such, KpOmpA is recognized by monocytes and dendritic cells (DCs) via two members of the scavenger receptor family (the lectin-like oxidized low-density lipoprotein receptor-1 or LOX-1 and the scavenger receptor expressed by endothelial cell-I or SREC-I) and is able to induce a TLR2-dependent proinflammatory response [55]. This inflammatory response includes supplemental PTX3 production via a positive feedback loop which, in its turn, promotes the original inflammatory response brought about by KpOmpA, in terms of inflammatory cell recruitment and inflammatory cytokine release. Due to PTX3 participation, this response is complement modified [56]. In murine Klebsiella pneumoniae infection, the difference between death and recovery relies on PTX3-evoked fine-tuning of the balance between tumor necrosis factor (TNF-α) and nitric oxide (NO) production. By (i) shifting the balance of these antagonistic mediators in one or another way and (ii) depending upon the inaugural inflammatory response which must deal either with a high or a low bacterial inoculum, PTX3 will either favor or disfavor the ability of the host to combat the infection [57]. Essentially, these principles hold true for any inflammation, be it of microbial or sterile origin. Examples thereof will be presented followingly.
12. Pentraxin 3 and Immune Responses in Aspergillus Fumigatus Infection
Aspergillus fumigatus is an ubiquitary fungus which elicits a broad spectrum of diseases in immunocompromised or atopic subjects, ranging from severe pulmonary infections to allergy. Aspergillosis is a major life-threatening infection in patients with defective phagocytosis, the hallmark of chemotherapy- or radiotherapy-induced neutropenia and monocytopenia [58]. From among inborn immunodeficiencies, chronic granulomatous disease (CGD) is of interest in this context. Pathophysiologically, this condition displays defective superoxide production by the enzyme NADPH. The clinical course is characterized by increased susceptibility to infections. Opportunistic pathogens such as Aspergillus fumigatus are involved. Prophylaxis with trimethoprim-sulfamethoxazole, itraconazole, and, in selected cases, administration of IFN-γ may be efficient, but often imperfect. Excessive inflammation is treated with systemic corticosteroids which, however, further suppress the patient's immunity. Gene-replacement therapy for patients lacking a suitable stem cell donor is still an experimental procedure. Neutrophils, although reduced in numbers and/or in function, are of paramount importance in the institution of a protective inflammatory response. Inflammation by itself may confer some protection. Notwithstanding, tight control of defense reactions is a vital condition. Unleashed inflammation is deleterious. On top of these problems, CGD patients may develop autoimmune diseases, a condition which mirrors generation of neoantigenic determinants, presumably by reactive oxygen and nitrogen species, which is the more so astonishing that the NADPH enzyme is functionally deficient [59].
In mice, genetic loss-of-function studies have yielded results that might be, at least in part, applied to humans. First, PTX3-knockout mice (ptx3−/−), in whom the gene encoding for PTX3 has been silenced, are highly susceptible to invasive pulmonary aspergillosis. The course of the disease recapitulates defective recognition and killing of aspergillus conidia by PTX3-deficient neutrophils, dendritic cells, and alveolar macrophages [60]. Second, the p47phox−/− mice closely mimic human CGD, most importantly the defective, albeit detrimental inflammation. Once these mice have been infected with Aspergillus fumigatus, their own production of PTX3 is both delayed and insufficient. Administration of exogenous PTX3 in early infection is able to rescue antifungal resistance and, at the same time, to restrain the exaggerated inflammatory response to the fungus by way of curbing the IL-23/Th17 inflammatory axis [61]. This beneficial reversal is produced via downregulation of IL-23 production by dendritic cells and epithelial cells, an effect associated with limited expansion of IL-23R+ γδ+ T cells. These cells are important producers of IL-17A, a mighty inflammatory cytokine and a neutrophil chemoattractant which is involved in many inflammatory diseases, once again either microbial (e.g., Borrellia burgdorferi, Mycobacterium tuberculosis) or sterile (atherosclerosis including its complications) in origin. Consequently to IL-17A decrease, protective Th1/Treg responses are upregulated [62].
To elucidate this positive point of return, it should be reminded that defective tryptophan catabolism contributes to excessive inflammation in CGD individuals infected with Aspergillus fumigatus. In immunocompetent hosts, tryptophan metabolism regulates both antimicrobial resistance and tolerance to inflammation-inducing microbial stimuli. Since superoxide is a cofactor of IDO, which is the rate-limiting enzyme in tryptophan degradation, superoxide-induced activation of IDO is a central mechanism by which an equilibrium between antifungal resistance and immune tolerance is achieved. The enzyme IDO represents both the host's effector defense mechanism and a means of properly balancing the generation of inflammatory Th17 and regulatory T cells (Tregs) [63]. Tregs and IL-17-producing Th17 cells call forth opposing responses in inflammation, including aspergillosis. Whenever harmful inflammation predominates, whether microbial or sterile in origin, this IL-17-driven inflammation is associated with a decrease in anti-inflammatory Treg cellular responses [64]. Basically, the same holds true for invasive aspergillosis as well as for human ischemia-reperfusion injury, no matter which organ is affected [65]. In all these cases, an attempt at a defense reaction translates into a control-evading detrimental inflammation. In terms of cellular adaptive immunity, expression of mRNA for transcription factors Tbet/Foxp3, which is indicative of Th1/Treg activation, is increased in CD4+ T cells from wild-type, disease-resistant mice. Conversely, RORγt/Gata3 transcription factor mRNA expression, which is indicative of the opposite Th17/Th2 activation, is increased in CD4+ T cells from disease-prone p47phox−/− mice. Early administration of PTX3 to p47phox−/− mice restores this malevolent balance in that it reverses the original ratio of the transcription factors: it increases the expression of Tbet/Foxp3 and decreases that of RORγt/Gata3 [66]. It is tempting to speculate that comparable effects of PTX3 would be operative in patients with myocardial infarction, but reliable proofs thereof are as yet lacking.
13. Acquired Cellular Immunity in Inflammation
It is well established that CD4+ T cells take part in the pathogenesis of atherosclerosis [67]. In addition to classical Th1 and Th2 helper cellular subsets, each producing its own set of cytokines which are mutually antagonistic, a third subset has been described recently, namely, the Th17 cells [68, 69]. These cells express proinflammatory cytokines of their own. The most important of them has been named interleukin- (IL-)17. Actually, IL-17 is a common denomination for a set of closely related cytokines referred to as IL-17A to IL-17F, respectively. From the clinical point of view, IL-17A and IL-17E appear to be the most active ones [70]. The orphan nuclear receptor retinoic acid-related orphan receptor γt (RORγt) has been proposed as the key transcription factor for the differentiation of the Th17 lineage [71]. Th17 cells have been shown to play a role in chronic inflammation which, historically, was attributed to Th1 cells. One of these conditions is atherosclerosis [72]. Recent studies found that Th17 cells and their effector cytokine IL-17 are really increased in peripheral blood of patients with atherosclerosis, including acute coronary syndromes [73, 74]. Pathophysiologically, the Th17/IL-17+ cells directly support the development of atherosclerosis in ApoE−/− mice. Herein, the amount of Th17 cells and of RORγt in affected vessels is proportional to the magnitude of the overall atherosclerotic burden. Both mediators are not manufactured in situ, as can be inferred by their respective behavior in ApoE−/− mice. The number of Th17 cells in spleens of young, not yet atherosclerotic ApoE−/− mice, has been proved comparable to that in healthy control animals. In ApoE−/− mice, the number of Th17 cells tended to increase as a function of time, tightly paralleling continuing development of atherosclerosis. Although CD4+ T cells are the main source of IL-17, they are not the only origin of this cytokine. Neutrophils, as well as the CD8+ and γδ+ T cells, were demonstrated to generate IL-17 in response to the inflammatory cytokine IL-15, just to give an example. Differentiation of mature Th17 cells depends on the stimulation with a "cocktail" of cytokines, namely, IL-6, TGF-β, and IL-21 and on the induction of their inherent transcription factor RORγt. On the other hand, IL-23 is indispensable to the achievement of mature Th17 phenotype and its stability under inflammatory conditions [75, 76].
The Th17/Treg equilibrium is vital to the control of inflammation [77, 78]. Its derangement will bring about destabilization of atherosclerotic plaques, the composition of which has been extended recently to include Th17 cells, the cytokine IL-17A, and the transcription factor RORγt. If the fragile Th17/Treg balance is lost, its new inadvertent ratio will call forth the onset of acute coronary syndromes (instable angia pectoris or acute myocardial infarction). In this context, patients experience significant increase in peripheral blood Th17 cell numbers, Th17-related cytokines (IL-17A, IL-6, IL-23) and RORγt levels. At the same time, there is a decrease in blood levels of Treg numbers and Treg-related cytokines IL-10 and TGFβ as well as of their transcription factor FoxP3. It may be soundly hypothesized that PTX3, which is endowed with the capacity to reverse this harmful inflammatory dysbalance in Aspergillus fumigatus infection by skewing the predominance of transcription factors (RORγt/Gata3 → Tbet/Foxp3) with consequent shift of their respective cellular subsets (Th17/Th2 → Th1/Treg), might bring about a comparable beneficial effects in this form of sterile inflammation. Nevertheless, it must be strongly pointed out that results yielded by experimental animals cannot by dogmatically extrapolated to humans, as attractive as they may appear [79].
14. Concluding Remarks
In both acute infections and acute coronary syndromes, the role of PTX3 appears to be primarily protective in that the long pentraxin dampens the inappropriate, exaggerated inflammatory response. On the local level, PTX3 released by PMNs or produced by monocytes/macrophages will abolish neutrophil recruitment and oxidative burst, a condition which kills bacteria by reactive oxygen species, while it inflicts collateral damage to the host. PTX3 co-operation with the adaptive immune system in defense inflammation which combats infection supports, in its turn, development of a protective Th1/Treg immune response while at the same time it limits harmful inflammation elicited by the Th17/Th2 immune response. Further studies are needed in this context to furnish data that would imply to which extent PTX3 might be employed therapeutically.
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- L. Yang, D. E. Anderson, C. Baecher-Allan et al., "IL-21 and TGF-β are required for differentiation of human 17 cells," Nature, vol. 454, no. 7202, pp. 350–352, 2008. View at Publisher · View at Google Scholar · View at Scopus
- E. Volpe, N. Servant, R. Zollinger et al., "A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human -17 responses," Nature Immunology, vol. 9, no. 6, pp. 650–657, 2008. View at Publisher · View at Google Scholar · View at Scopus
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- E. V. Acosta-Rodriguez, L. Rivino, J. Geginat et al., "Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells," Nature Immunology, vol. 8, no. 6, pp. 639–646, 2007. View at Publisher · View at Google Scholar · View at Scopus


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Learn German as a second language with Langenscheidt's comprehensive German – German Dictionary. Comprehensive German vocabulary with 60,680 entries, 66,000 words and phrases and over 63,000 example sentences. Learn German with Langenscheidt, Germany's No. 1* dictionary publisher.
This app ist the digital equivalent of "Langenscheidt Großwörterbuch Deutsch als Fremdsprache".
THE GERMAN DICTIONARY FOR GERMAN LANGUAGE LEARNERS • German – German entries• Over 65,000 words and phrases• Over 63,000 example sentences and over 30,000 word combinations to actively expand your vocabulary• The latest German vocabulary from all walks of life• Straightforward definitions of German words • Comprehensive grammar und over 2,100 extra hints for correct usage• Specifically designed with learners of German as a second language in mind• Ideal language course companion• Morphology module to translate words in any grammatical form (for Englisch, French, Spanish and Russian).
USE GERMAN DICTIONARY OFFLINENo internet connection required. The German dictionary app also works in flight mode and abroad without roaming fees.
HAVE GERMAN WORDS READ ALOUD TO YOURead-aloud functionality demonstrates the correct pronunciation of German words. This way, you learn and use German words quickly in everyday situations.
----------SEARCH AND FIND GERMAN WORDS• Full text search • NEW! Search for Anagrams • NEW! Search within entries to narrow search results and search longer entries more quickly • Placeholder search• Search for similar words in case of incorrect spelling
HANDWRITING RECOGNITIONWrite words on the display instead of typing them. This makes searching easier and helps find German words more quickly.
VOICE RECOGNITIONUser your microphone and speak the words you want to search for. This way you save time as opposed to having to type them. This is especially useful for words that you are unsure of how they are spelt.
IMAGE RECOGNITIONTake a photo of the text you want to translate and find it with the help of Google Goggles.
COPY AND PASTEThe simple copy-and-paste functionality allows you to copy German words and phrases from your browser or email to the clipboard. On opening the German dictionary app, the copied words are automatically translated.
YOUR PERSONAL GERMAN VOCABULARYThe favourites list allows for quick access of German words you search for frequently: Save important words to your favourites for quick and easy access.
SEARCH HISTORYThe search history displays the last 100 words you looked up: Access your last searches in the German dictionary by quick-access.
WORD OF THE DAY WIDGETLearn a new German word every day with the word-of-the-day widget, and broaden your German vocabulary step-by-step.
----------* according to market research institute GfK Entertainment GmbH, Langenscheidt ranks #1 in dictionary sales in Germany.

subset: commoncrawl


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Hello All,
This Saturday, Gamers Across the world, will unite in a 24 hour gaming marathon to fight pediactric cancer. More information can be found at this link: https://www.hospitalshelpingkids.org/ExtraLife/default.aspx
I am participating in this event on Saturday, October 16th, 2010. You can donate to mine, or anyones page, since all of the money goes to the Children's Miracle Network.
Here is the link to my Extra Life Page: https://www.hospitalshelpingkids.org/ExtraLife/m.aspx?i=1972390EB+1+D5BFA
Thank you and updates on the blog will be coming more regularly from now on,


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360 Technical Center Solutions (360TCS) has opened a new data center in Lombard, Ill. and is focusing on providing high-density data center space to Chicago-area financial firms. The facility has opened with an anchor tenant in Wolverine Trading, a Chicago trading specialist that's also an equity investor in 360TCS.
At 8,000 square feet, 360TCS is a relatively small facility, and will be built out in two phases. "We have a unique niche target market," said Don Welbourn, Director of Sales for 360TCS. "We are not focusing on selling large contiguous footprints. This facility will appeal to a specific type of client. With the center's high density capabilities, equipment that would occupy 10 or more cabinets in most facilities can be compressed in to three or four."
The growth of low latency trading has boosted business for providers like Equinix (EQIX) and Savvis (SVVS) in the New York and Chicago markets. Wolverine provides technology solutions for high-performance trading, including real-time market data feeds that enable algorithmic trading. The availability of these data feeds is a key step in attracting trading operations and building a financial ecosystem within a data center.
"A network design capable of delivering low latency connectivity to all of the major exchanges in the U.S. and Europe provides a tremendous advantage to businesses that rely on receiving this data," said Welbourn. "The infrastructure of 360TCS was designed specifically to meet the needs of companies in the financial industry."
That approach made an impression on Wolverine. "We have space in data centers in several cities in the U.S. and Europe, and in most cases we have to adjust our requirements to meet the data center's limitations of available space, power, and connectivity," said Jim Michuda, Partner at Wolverine. "At 360TCS, the needs of a technology driven financial firm were paramount in the data center's design."


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- Police identify victims killed in first two fatal crashes of 2019
- Cedar Park police seeking help finding missing elderly man
- One killed, 3 injured in southwest Austin accident
- Major League Soccer officially announces Austin FC as 27th club
- Pedestrian struck, killed on Interstate 35 in North Austin
- Body of missing Kyle man recovered from Blanco River
- Southeast Austin shooting sends one to hospital
- One killed in fatal motorcycle accident west of Round Rock
- Austin-area gas prices drop again against lower demand
- Suspect shot, killed in San Marcos officer-involved shooting
- SpaceX to build Mars ships in Texas, not Los Angeles
- Amid shutdown, Abbott sidesteps border wall debate
- Missing 12-year old from George West found in Laredo, officials say
- Woman drinking wine from Pringles can banned from Walmart
- DNA of wolf declared extinct in wild lives on in Galveston pack
- How long can O'Rourke wait as 2020 pace picks up around him?
- Former Obama housing chief Julian Castro joins 2020 campaign
- Tarrant County GOP rejects outing vice chair over his faith
- Laredo border agent pleads not guilty to killing 4 women
- Texas border landowners prepare wall fight as Trump visits
- Body cam video shows cop fatally shoot 14-year-old as he ran away from police
- Third annual Women's March ascends upon cities amid controversy
- Winter storm could dump more than a foot of snow on interior Northeast
- Former Chicago cop sentenced to 81 months in prison for murder of African-American teen
- 9-year-old girl breaks into house to save grandmother
- Minnesota mom charged after car seat falls out with child in it
- Man charged in alleged drugs-for-weapons deal with al-Qaeda-linked group
- Women's March organizers respond to controversy leading up to rally
- Overlooked evidence in Hania Noelia Aguilar murder case leads to investigator's firing
- Former Chicago police officer to be sentenced for Laquan McDonald murder
Talk Poll: As the partial shutdown drags on, should President Trump hold firm on the border wall?
Austin, TX VIEW FULL FORECAST
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12/16: The Bucket Show
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Sunday, December 16th
Noble Capital Radio Hour, for December 16. The show's hosts are always talking about buckets - income buckets, that is. In this episode, we drill down into what income streams you can use to retire confidently.


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Nov 27th 2013
Security Now 432
Coin, Patent Trolls, and More
Hosted by Steve Gibson, Leo Laporte
More about Coin, an update on CryptoLocker, a look at a high profile patent troll case, and more.
Records live every Tuesday at 4:30pm Eastern / 1:30pm Pacific / 21:30 UTC.
Hosts: Steve Gibson with Leo Laporte Following another week overfilled with interesting security-related news, Steve and Leo spend an hour and a half diving deeply into an updated (and likely very close to correct) understanding of the COIN payment card, news on the CryptoLocker front, a close look at a patent troll case that has so far done the wrong way, and much more. Download or subscribe to this show at twit.tv/sn. We invite you to read, add to, and amend our show notes. You can submit a question to Security Now! at the GRC Feedback Page. For 16kbps versions, transcripts, and notes (including fixes), visit Steve's site: grc.com, also the home of the best disk maintenance and recovery utility ever written Spinrite 6. Bandwidth for Security Now is provided by Cachefly. Please take the TWiT Audience Survey at http://twit.tv/showsurvey. It only takes a few minutes and we'd love to know what you think. Running time: 1:34:25


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You are hereHome ›
Narrow Search
Now showing results 1-8 of 8
James Webb Space Telescope (JWST) Lithograph and In Search of ... the James Webb Space Telescope classroom activity
The lithograph features illustrations, statistics and science goals of the James Webb Space Telescope. The accompanying classroom activity prompts students to use the images and text to generate questions about the telescope. Students then research... (View More) those questions on the Internet and present their findings. (View Less)
Materials Cost: Free
This investigation is based on the GISP2 H-core data collected in 1992 adjacent to the GISP2 Greenland summit drill site. Students examine the seasonal/annual nitrate record and use information from known volcanic eruptions to date the unique... (View More) signature of the Icelandic volcanoes. Data is also provided for known volcanic eruptions from other latitudes which can be used throughout the activity to date major conductivity spikes to further refine the time locations. Educators can use the investigation as an application of absolute and relative dating activity (a skill taught within many science disciplines). It can also be used as an application of the cryosphere and ice cores, atmospheric chemistry, meteorology and world-wide climate patterns, geophysics involving the polar regions and the Van Allen Radiation Belts, or astronomy and the impact of extraterrestrial materials on planet Earth. (View Less)
This textbook chapter introduces the concepts of static and dynamic equilibrium, and discusses contemporary climate change. The greenhouse effect is presented in a discussion of Mars, Venus and Earth, the "Goldilocks" planet. Two investigations... (View More) support the chapter. The resource includes links to current news articles, and a suite of pre- and post-unit assessments. A teacher's guide supports classroom use. This is the sixth chapter in the unit, Energy Flow, exploring the flow of energy through the atmosphere, oceans, land, and living things over short and long timescales. The resource is part of Global System Science (GSS), an interdisciplinary course for high school students that emphasizes how scientists from a wide variety of fields work together to understand significant problems of global impact. (View Less)
This textbook chapter presents ocean and wetland ecosystems, and describes how floating plastic trash endangers aquatic species. Oceanographer Jacques Cousteau is profiled. The resource includes a student action plan to reduce waste in their... (View More) community, a link to current news articles and a teacher's guide. This is the seventh chapter in the unit, Losing Biodiversity, examining the endangerment and extinction of entire species of plants and animals throughout the world due to human actions. The resource is part of Global System Science (GSS), an interdisciplinary course for high school students that emphasizes how scientists from a wide variety of fields work together to understand significant problems of global impact. (View Less)
This textbook chapter summarizes the changes in the ecosystems found in the world's forests. This is chapter 2 in the unit, A New World View, which introduces global systems science, emphasizing the concepts of environmental diversity, Earth as a... (View More) system, and sustainability. The resource includes a textbook chapter, integrated hands-on and inquiry activities, links to current news articles, and a suite of pre- and post-unit assessments. A teacher's guide supports classroom use. The resource is part of Global Systems Science (GSS), an interdisciplinary course for high school students that emphasizes how scientists from a wide variety of fields work together to understand significant problems of global impact. (View Less)
Materials Cost: Free per student
In this activity, students learn that infrared light is reflected in the same manner as visible light. Students align a series of mirrors so that they can turn on a TV with a remote control when the remote is not in a direct line with the TV. As a... (View More) result of their experiment with reflection, students deduce that infrared light is another form of light and is a part of the electromagnetic spectrum. Section 1 of the activity guide includes teacher notes, information on materials and preparation, student misconceptions and a student pre-test. Each activity section also includes teacher notes, student activity sheets, and answer keys. This activity requires a TV and remote control. It is the third of four activities in Active Astronomy, which are designed to complement instruction on the electromagnetic spectrum, focusing on infrared light. (View Less)
Materials Cost: Free
This activity is about planetary climate. Once familiar with the factors that determine a planet's surface temperature, learners will use an interactive spreadsheet model of a planet's atmosphere to determine if greenhouse gases, luminosity of the... (View More) source, the distance of the planet from the source and the albedo of the planet can be manipulated so that the average surface temperature on Mars or Venus could support human life. Learners will then be asked to make some conclusions about these methods and suggest improvements for the spreadsheet model (see related resources for link to this model). The activity requires use of Microsoft Excel software. This is Activity D in the fourth module, titled "How do Atmospheres Affect Planetary Temperatures?," of "Earth Climate Course: What Determines a Planet's Climate?." (View Less)
Through a field trip along a local water course students will conduct a visual survey to discover information about local land use and water quality. They will document their findings with mapping and compilation of a river profile and use this... (View More) initial reconnaissance to raise questions about local land use or river water quality that require investigation. This activity is part of the Ground Truth Studies Teacher Handbook, which provides more than 20 activities to build student understanding of global change and remote sensing, and includes background chapters for teachers, glossary, and appendices. (View Less)
Materials Cost: Free per group of students


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Legislation and Policy
On this page you will find links to many federal and state government agencies as well as nonprofit organizations, commissions, and networks involved in policy issues such as pending legislation and children's rights at school.
National Resources
Asthma and Allergy Foundation of America (AAFA)
This non-profit supports policies that aim to improve access to health care, increase funding for medical research, and promote a higher quality of life for individuals with asthma and allergies.
Allergy and Asthma Network, Mothers of Asthmatics
This national nonprofit network of families offers information about living with asthma, including information about policy issues such as pending legislation and children's rights at school.
- AANMA Advocacy Page
This site details issues that affect families with asthma: Allergy and Asthma Network, Mothers of Asthmatics (AANMA) position statements, important legislation alerts, and updates.
American Lung Association
The American Lung Association (ALA)'s mission is to prevent lung disease and promote lung health. ALA programs seek to influence the development and enforcement of laws and regulations at national, state, and local levels, providing authoritative information to policymakers. These include the landmark federal Clean Air Act and the law prohibiting smoking on domestic passenger airline flights.
CDC's Public Health Law Program
CDC's Public Health Law Program, whose mission is to improve the health of the public through the law, offers resources on public health issues, including asthma.
- Right to Carry and Self Administer Asthma Medication in Schools—Legislation
This site provides selected asthma-related legislative measures addressing the right to self administer asthma medication and carry inhalers in schools.
Department of Health and Human Services
- Healthy People 2020 Objectives—Respiratory Diseases
This site contains the Healthy People 2020 national health objectives for asthma.
Library of Congress: THOMAS, Legislative Information on the Internet
This site provides information on the U.S. Congress and a searchable database of federal legislation.
- U.S. Legislative Branch
This site provides links to information about the federal legislative branch, information about the legislative process, and a searchable database of legislative branch Web sites.
State and Local Resources
Library of Congress: State and Local Governments
This site provides a meta-index of state and local government information and direct links to state government Web sites.
National Association of State Boards of Education
This association serves and strengthens the state boards of education in their pursuit of high levels of academic achievement for all students.
- State School Health Policy Database
This site allows you to search by state or by topic to find information about state-level school health policies, including asthma policies.
National Conference of State Legislatures
This bipartisan national forum allows state lawmakers to communicate with one another and to share ideas on various topics, including asthma.
- Asthma Web Resources
This site includes links to policy briefs on asthma, analyses of state legislation, and a searchable database of state legislation and statutes.
This Washburn University School of Law Web site, WashLaw, provides information about state governments and legislation.
- Page last reviewed: April 24, 2009
- Page last updated: June 24, 2014
- Content source:


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You are here
T-Tennis stars obtain injunction against association
T&T's most decorated table tennis players Dexter St Louis and his step daughter Rheann Chung have obtained an interim injunction against the T&T Table Tennis Association (TTTTA) as they challenge their exclusion from the team representing this country at the 2018 Commonwealth Games.
Justice Eleanor Donaldson-Honeywell granted the injunction, which bars the TTTTA from taking further action on the selection issue, when the duo's lawsuit came up for hearing in the Port-of-Spain High Court yesterday morning.
The injunction will last until the next hearing on January 24, when Donaldson-Honeywell will consider if to extend it. The association's entire executive was present for the hearing, but both St Louis and Chung were was absent as they current live in France. The parties have tight deadline to resolve their dispute as the games will be held Gold Coast, Queensland, Australia, between April 5 and 15, with representatives being required to register several months before.
During yesterday's hearing, Donaldson-Honeywell gave the duo time to file their response to the TTTTA's defence to the allegations that were raised by them.
In their lawsuit, St Louis, 50, and 33-year-old Chung are questioning the process used by the association to select 19-year-old Aaron Wilson and 21-year-old Yuvraj Dookram to the team and Arun Ramnarine as reserve.
They are seeking damages for breach of contract, conspiracy and unlawful interference and an order that the issue be resolved through the T&T Olympic Committee (TTOC)'s arbitration process.
In defence of the lawsuit, the TTTTA is claiming that the duo was informed via email of the selection criteria and chose not to participate. It is also alleging that they only decided to challenge the process after it was completed. The TTTTA is also claiming that it had closely followed the TTOC's guidelines and deadlines in making its selection.
It is also claiming that arbitration is not an option as such an only be initiated by the association under the TTOC's constitution. St Louis and Chung are being represented by Mathew Gayle, Sheriza Khan and Dr Emir Crowne, while Dinesh Rambally, Kiel Tacklalsingh and Stefan Ramkissoon are representing the TTTTA.
User comments posted on this website are the sole views and opinions of the comment writer and are not representative of Guardian Media Limited or its staff.
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I found this thread while looking for a solution but still haven't found one so I'm posting my scenario!
eCard 4.5 is working fine. But, the eCart Object button on the insert toolbar doesn't do anything. If I create a new page I can't add the object. I've done a number of sites and I have to keep copying/pasting code from other pages to get the object there but I figured I should make contact to see why it's not working the way it should.
I have DW/CS3 latest build running on XP Pro.


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Tonight's card is a very simple card. I decided to use one of my favourite stamp sets "Nature Walk". I absolutely love the bird stamp from this stamp set. I think it is so beautiful and elegant. I didn't want to over do it so I have used natural tones and paper from the "Pocketful of Posies" designer series paper set. I have used the crumb cake seam binding ribbon to put a simple embellishment on the card. All very simple. That is all I have time for tonight. Cheers Nicky.
Nicole Ryan Independent Stampin' Up!® Demonstrator | For all your papercrafting needs, Australia wide
Tuesday, June 19, 2012
A simple card - card 16
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Institutional Communications
Bureau of Mines Building, Room 137
Laramie, WY 82071
Phone: (307) 766-2929
Email: email@example.com
UW's Van Aken Just Misses CNFR Short Go Bid
There's no doubt that University of Wyoming senior Clayton Van Aken will be thinking about his missed steer earlier in the week. It cost him a chance to reach the short go in team roping at the College National Finals Rodeo (CNFR).
Despite a near-flawless run Thursday night that resulted in a 5.9-second time, Van Aken and partner Kyon Kreutzer of Northeastern Junior College just missed qualifying among the top 12 teams that will advance to Saturday's championship round.
Their final attempt was one of the fastest for team ropers Friday night. After their third run, the pair moved up to the No. 13 spot, leaving them just out of the running.
"They had a good round, and it's just too bad that they won't make it to the finals," UW Coach George Howard says. "But those things happen."
This week marked the fourth consecutive year the Descanso, Calif., senior qualified for the CNFR. He reached collegiate rodeo's main competition as a two-event contestant, but he and Kreutzer missed out on their second-round steer, sandwiched between two solid runs.
"If he could have caught three, he would be sitting in the top three right now," Howard says.
Instead, the program's all-time leading men's scorer saw his UW career come to an end. Van Aken also competed this week in tie down roping, but managed just one good qualified time.
Van Aken was the only UW team member up Thursday night. Two of his teammates will compete Friday night, with one of them still in contention for a short go bid.
Senior Wyatt Clark of Wellfleet, Neb., needs to reach the whistle to qualify in bareback riding. He has 147 points on two.
Easton, Colo., junior Kade Merritt finishes his three guaranteed rounds in team roping. He and partner Jade Schmidt of Gillette College have yet to secure a qualified time.
Brit Ellerman of Fort Lupton, Colo., will compete in Saturday's championship round with team roping partner Seth Andersen of Gillette College. The pair remained sixth in the average after Thursday's performance.
Institutional Communications
Bureau of Mines Building, Room 137
Laramie, WY 82071
Phone: (307) 766-2929
Email: firstname.lastname@example.com


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Happy Teddy Bo Tuesday!!
Good Morning Teddy Bo-ettes.....how are you all this morning?!??!?! It's another 'fresh' day here at the Towers...it's trying to snow again...so with all this bad weather and our design team's reluctance to wear much clothing or go outside without a tankful of schnapps!!....we've been doing some Spring Cleaning this week. Let me tell you....there are cobwebs in places you WOULDN'T expect them...isn't that right Colette!!?!?!?
Our Blog hop was a great success but we still have one or two to claim their prize...so please check the prize-winners post to see if you were one of our winners.
Helle (our resident 'cocktail shaker') has been walking the floorboards at night awaiting the birth of her first Granddaughter......well.....thank goodness this little angel has finally arrived as Helle was driving us all potty (she has a VERY squeaky floorboard in her room and kept picking that one to walk over!!) So how delighted was she when this photo arrived on the Teddy Bo T'internet to show us what she looked like....
She's only 3 days old here and isn't she just beautiful. Little Jessica doesn't know us all yet (we'll break her in gently)...but her 'extended' Teddy Bo family want to wish her and her family lots of cuddles and kisses...we have packed Helle off for a couple of days back home to visit this precious little baby and have warned her she must make her partner Freddy take LOTS and LOTS of pictures.....xxxx
SO...what's NEW this week
and of course......with all the broken nights of sleep and lots of Spring cleaning getting done...the Design Team appear to have magically made another collection of wonderful cards for us all to view!!!
and of course......with all the broken nights of sleep and lots of Spring cleaning getting done...the Design Team appear to have magically made another collection of wonderful cards for us all to view!!!
Image is TEDDYBEA_183
Coloured with Copics
Papers from Vibece Spigset and some leftovers from MME
Paperdoily behind. All panels are machinestitched.
Flowers handmade with a Marianne die and the butterfly is a CL die.
Metalframe with a Whimsy text inside
Teddy Bea 184
Me to You papers 'Spring Chic'
Copics and Promarkers to colour
MS Punch, Twine, Buttons and PC sentiment
Liz x
The text says.."one shall clean....BUT NEVER ON A BIRTHDAY"
Magnolia paper
Bo Bunny paper
Magnolia tag
Metalflower from PyHobby(roses and pearls too)
I´ve used:
Teddy Bea 183
Spellbinder Label five
Spellbinder Floral Doily Motifs
Paper from Pachela
This started off as a quick and easy card, but then I decided to make my own embellishments, a sponge, a feather duster and a dishcloth. Of course I had to add a bit of bling to my duster LOL!
Image - TBEA_183 coloured in Photoshop
Striped paper in WORK - Echo Park - Life is Good
Insert papers and sentiment-Papercraft inspirations free download.
I´ve played with the sweet image TeddyBea_183
colouring as always with Prismas
sentiment by Motivet
cardstock Bazzill
design paper by Maja Design
embellies: flowers, pearls, swirl
I hope you´ll like my card :0)
Hugs Nicole
I've made myself a new notebook for my lists :c)
Image: TEDDYBO_177
Paper: Pink Petticoat
Alphabet: Sizzix Man Oh Man
Teddybo-101 image
Colored with Promarkers
lime zest
soft lime
ice grey1,2,3,4
glitter paper
simple stories paper
flower trim
rhinestones /stickles
TEDDYBOBEA_102 Coloured with copics.
Glamour dust added to his pom pom and glossy accents to his bubbles.
Flowers were a gift from a good friend and they are a mix of blue and white, with a pearl in the middle.
Silver swirl on front is Cheery Lynn.
Martha Stewart double loops punch.
Memory Box die on the inside is valerian flourish.
Paper is MME Lost and found.
TeddyBoBea 102
Echo Park "Splash" DP
NB Standard Circles
Sentiment is "Birthday Letter Seals" from Raindrop Echo Designs w/Whimsy
Studio G Alpha Stamps
Just the Edge Bazzill Basics
Ranger Distress
Colored Pencil and Gamsol
Royal Coat Plaid Dimension
Here I am with a new card, this time with cute Olliphant,TeddyBoBea 102
Colored with Prismacolor
Pattern Paper from Pion Design
Flowers from Kort & Godt, Storyteller and WOC
I bought myself a new dies, but can not remember who made this one ...
"A little hello" is the text on the stamp
I have also dotted the edges with a stamp from Stempelglede
Not long left now to enter our
Anything Goes
challenge. Your entries must be in by Midnight GMT on Sunday 5th February. The lucky winner will receive their choice of the
(10 graphics from the Teddy Bo store)
And remember you only have a few days left to qualify for our Teddy Bo & Co FIRST BIRTHDAY CANDYSo pop this on your blog......come back to http://teddybochallenge.blogspot.com/2012/01/teddy-bo-tuesday-first-birthday.html and tell us you've done in so that we can pick our winner....remember, you have to post this on your blog and tell us you've done it to qualify!!!
Catch you soon.....Gayle and the Gang...x


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Asus 670 BSOD's on startup after driver install
need help just upgraded to a 670 CUII and it BSOD during windows startup the restart after the drivers are installed :(. Tried both asus and Nvidia drivers. any help would be great
Did you clean the drivers from your AMD card in safe mode before you shut it down and installed the Nvidia?
That I did my good sir, still having the issue just ran out to my computer storage room and grabbed the driver disk remember that my old 6870 only would install the first time with the asus driver disk maybe this Asus 670 is just buggy like it was that way.
If you can run a GPU benchmark in Linux or a separate Windows install, you can pretty much guarantee it's a driver issue.
Looks like I am SOL time to try a reload if that fails nvidia will again be on my hated list and I will go get a 7950
I had a crash issue with my 670 but it would get into windows first... i found the GPU tweak software was the cause..
It is possible that you got unlucky and it's just a bad card... Which can happen with any type of card from any manufacturer..
If possible try it in a different box.
... 4 machines and 2 reloads I got a bad card... I will advance swap for one more but am really disappointed this was supposed to be Nvidia's saving grace for me... I was going to swap from my 6970 and almost 6 solid years of ATI/AMD only love over to all Nvidia in my house but if I get another one back failed. I will never look back:doh:
Dammm. Was going to suggest driver sweeper in safe mode due to similar issue but if card is bad card is bad.
good plan, I tried Drive sweeper too :thumb: great minds think alike but sadly just DOA new card is here going to try it in 3 hours haha
Ended up being my server, it wont play nice with any Kelper cards, and for some reason Nvidia cards only play at half power but when I put a AMD card in it runs way smoother so back to my 6970 for now:) still a great card though
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Mortal Kombat X Kombat Pack 3 v1.17 Crack Full Keygen
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