Cite this article as: Zhou J, Zhang X, Wang Z, Zheng B, Ernberg I, He Z, et al. Exosomes: Secreted Membrane Micro Vesicles that Mediate Intracellular Communications. Clin Oncol. 2016; 1: 1151.
Exosome is an nano-particle with diameter of 40-100nm, generated in endosomes with bioactive molecules incorporated into lipid bilayer envelope. The micro vesicles migrate and are fused with membrane, then released to intercellular space. The compositions of lipids, protein and microRNAs in exosomes exert different effects on the cells which capture the microparticles. They impact on the host immune response against viruses and tumors, and interactions between host and invading viruses, as manifested by facilitating or suppressing viral infection. The oncogenic proteins and miRNAs encoded by Epstein Barr virus contained in exosomes contribute to the transformation of the surrounding recipient cells, and exosomes containing genomic products of HIV faciliate or suppress the viral infection. In view of the action of immune regulation and combating invading pathogens, exosomes show promising in antitumor and antiviral vaccine development.
Previously known as particles containing disposals of waste from cells, exosomes, a type of extracellular vesicles (EV) has been identified as a ultra-structural particle that convey messages to deliver to recipient cells. EDVs differ in size, origin, and inside components. The exosome is an EV of 40-150nm, formed as endosomal particle . EVs play a role in the intercellular communication, through the transfer of biologically active molecules of lipids, proteins and microRNAs (miRNAs) . As other type of EV, exosomes comprise lipid bilayer envelope, and enclosed compositions of lipids, proteins, and micro RNAs (miRNAs). They are exocytose on fused with the cytoplasmic membrane, and released to intercellular space, to exert different types of biological activities, like regulation of neuronal function and immune response, transmission of viral infection [3-5], and modulation of growth and proliferation of the surrounding cells which capture them. The viral proteins and nucleic acids are delivered by exosomes from infected cells to uninfected; this process is implicated in the spread of the infection  host antiviral immune response , and also contributes to such events like viral tumorigenicity [8,9]. A crucial role for exosomes in the viral life cycle as well as antiviral and antitumor immunity has been suggested.
Bioactive materials contained in exosomes are delivered from one cell to another [2,10-12]. The capture of exosomes by recipient cells is determined by fusion of vesicles to with cellular membranes mediated by a group of protein, tetraspanins, expressed on the EV membrane [13,14]. These molecules, as well as molecules enclosed in EVs (e.g., transcription factors and cytokines), constitute signals that can affect the function of recipient cells. Proteins on the surface of exosomes also determine adhesion to the plasma membrane of specific target cells. The intercellular adhesion molecule 1 (ICAM 1), present on dendritic cell (DC)-derived EVs, mediates EV recruitment by activated T cells and other DCs[15,16]. The combination of integrin proteins on tumor cell EVs was implicated in the delivery of exosomes to specific target organs, such interactions facilitate metastasis.
Exosomes are micro vesicles at nanometer scale, formed by the fusion of the endosome vesicles with membrane; the particles are surrounded by a phospholipid bilayer (approximately 50–100nm in diameter), with size range roughly overlaps that of the viruses [18,19] they are secreted by a diverse range of cell types, released to the intercellular environment, and some migrate to distal site with circulation. Molecules of lipid, proteins, and microRNAs with biological activities are incorporated into these particles during the biogenesis of exosomes. Exosomes have been predominantly characterized in the immune competent cells including antigen presentation cells (dendritic cells, macrophages), T cells, B cells, and tumors, and exert functions of exosomes include antigen presentation  and immunostimulatory and inhibitory activities .
An early endosomes contain only few vesicles in their lumen, and the vesicles accumulate during the maturation of endosomes. The late endosomes are increased in size and accumulate internal vesicles, and are hence called Multiple Vesicle Bodies (MVB). During the maturation of late endosomes, biologically active molecules including the protein and lipid compositions in the small bodies are incorporated in exosomes, and exert their functions when released to extracellular microenvironment. Two steps of event occur during the protein sorting: The first step is the lateral segregation and selection of the membrane, and the second one is the inward budding of the vesicle with the concomitant incorporation of the selected cargo . The surface molecules including receptors could also be engulfed by cytoplasmic membrane, to form endosome.
Exosomes are regarded as the source of self-antigen for modulating the immune response against various self-tissues, notably tumors. The binding of exosomes to target cells in which the regulatory effects to be mounted involve the interactions of them with a class of surface molecules acting as receptor, and the target cells include antigen presentation cells (APC) in the marginal zones in the spleen, and follicular dendritic cells in the B cells region in the lymph nodes. [15,21-25]. Macrophages that capture exosomes are present in the marginal zone of the spleen and the lymph node sinus. And sialoadhesin (CD169; Siglec-1) captures B cell derived exosomes through α2,3-linked sialic acids expressed on their surface. Research suggested that Cd169 plays an essential role in the capturing exosomes, and immune response against exosomal antigens mediated by CD169 .
Table 1: Programs of EBV infection in latency and associated diseases.
Note: a: ref.4; 1b: ref.42; c: ref. 43; d: ref 44; e: ref 45.
Programs of EBV infection in latency and associated diseases.
Exosomes, are recognized as a means of intercellular communication. The most important signals transduced by exosomes include immunoregulation. A major group of antigen presentation cells, dendritic cells emit signal to activate T cells, to mount host defense against tumors and viral infection, and tumor derived exosomes, play a role in counteraction of antitumor immune surveillance by the host, the activities are exerted by blunting specific T cell-mediated cytotoxicity and skewing innate immune cells towards a phenotype to support tumorigenicity . In addition, the signals delivered by exosomes also modulate angiogenesis, and remodeling stroma, hence favors tumor the onset of metastasis and contributes to tumor progression.
Human in vitro generated dendritic cells and the exosomes they release are potential tools for the modulation of immune responses. Monocyte-Derived Dendritic Cells (MDDCs) and their exosomes have been characterized . When peripheral CD14+ cells were co-incubated with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (conventional MDDCs) or with IL-4 and IL-3 to generate immature MDDCs, The IL-4/IL-3- generated MDDCs had significantly lower percentages of CD1a+, CD40+ and CD80+ cells and a higher percentage of CD86+ cells as compared with conventional MDDCs. And they had significantly higher densities of Major Histocompatibility Complex (MHC) class I [human leucocyte antigen (HLA)-ABC], MHC class II (HLADR), CD11c and the tetraspanin CD81, more efficient than the conventional MDDCs at inducing interferon (IFN)-gamma release in response to viral peptide. Thus, phenotypic ally the exosomes largely reflected their MDDCs of origin. The findings suggested development of DC- and exosome-based therapies.
Compositions frequently found in exosomes are MHC class I and MHC class II molecules. It has been reported that these molecules cause immunosuppression [29- 31]. In mice, exosomes, especially from DC, have been shown to reduce inflammation due to IL-10, B7, and MHC class II. Exosomes from plasma in mice can contain other protein markers such as CD71, FasL (also aids in suppressing inflammation), and CD86 .
Exosomes from tumor cells can contain transforming growth factor-b (TGF-b) on the lipid surfacetosuppressTcells. . Manycytokinesin macrophage-derivedexosomes, suchasCCL3, CCL4, CCL5, TNFa, G-CSF, CSCL2, and IL-1RA, causeimmunestimulationin target cells. Pathogen-associated molecular patterns (PAMPs) are also packaged into the exosomes from bacterially-infected cells to cause a faster immune response . Exosomes from B cells can contain LAMP-1, CD20, BCR, various tetraspanins, as well as heat shock proteins. Overall, immunoregulatory molecules incorporated into the exosomes may cause both immuno-suppressive and immuno-activation effects depending on their composition and cellular source of the exosomes.
Exosomes released from tumor cells and other types of cells contributes to the immune suppression through interactions with target cells. When co-cultured with antigen specific dendritic cells, CD+8 T cells are stimulated to produced exosome targeting to the CLT specific for the same antigen, including what is expressed on melanoma cells . The inhibition, however, is reduced by LFA-1 expression. T cell derived exosomes expressing a death ligand, Fas L has been shown to promote the invasion of cancer cells in vitro through Fas/Fas ligand interaction. The exosomes increased the amount of the inhibitors of FLICE/caspase-8 and subsequently activated intracellular pathways of NFkappaB and ERK, to elevate matrix metallothionase 9 (MMP9). A Fas-MMP9 axis triggered contributing to tumor invasion, triggered by T cell derived exosomes is suggested . The finding suggested a T cell exosome in suppression of antitumor immunity, Table 1 as well as a possible use of the exosomes in treatment of autoimmune diseases.
Their release by tumor cells may represent the future for targeting therapeutic interventions and for development of multiplexed diagnostic biomarkers.
Exosomes are released by a great variety of cells, including normal cells of either hematopoietic or epithelial origin, but also tumor- and virus-infected cells [37,38]. The exosomes derived from Natural Killer (NK) cells are thought to play pivotal roles in both innate and adaptive immunity. Data suggested that activated and resting NK cells freshly isolated from the blod of healthy donors, express protein markers of NK cells, including CD56 and also proteins participating the cell death process, for example, Fas ligand and perforin molecules. Molecules involving the functions of NK cells, including the rceptor NKG2D, its multiple ligands, MHC class I-related chain A and B (MIC A/B) form a powerful stress-induicble danger detector, targeting various micro environmental stress including infections, inflammation and malignant transformation. It plays a vital role in the host immune surveillance against tumorigenesis. These molecules are enriched in the endosomal compartment of the tumor cells, and released in the form of exosome to extracellular environment, including intercellular space and body fluids . The nanovesicles display cytotoxicity against tumor cells, as well as to activated immune cells. The cell type specificity may be based on the surface molecule profile. And the molecules expressed on the target cell surface may guide the uptake of the exosome: by tumor cells but not by resting peripheral hemopoietic cells. The work proposes an important role of NK cell derived exosomes in immune surveillance and homeostasis, and the use of exosome in the future therapeutic approaches in various diseases, including cancers and viral infection.
During the viral latency of human viruses, viruses, notably herpes viruses exploit cellular biosynthesis machinery to support a longlasting, well-balanced infection with their host. Human herpes virus 4 (HHV4) or Epstein-Barr virus (EBV) is a human herpes virus which establishes life-long latent infection in the host, playing pathogenic role in a variety of malignancies, ranging from lymphomas arising in immune suppressive individuals infected by HIV or receiving immune inhibitors on organ transplant to Burkitt Lymphoma (BL), undifferentiated nasopharyngeal carcinoma (NPC) and other types of malignancies. EBV genomic products are detectable not only in tumor cells, but also in extracellular milieu, in free soluble form or loaded in exosomes.
EBV genome codes for a number of products of miRNAs and proteins with transforming potential. The viral genetic products are expressed in a pattern dependent on latency types. Different host ranges of the two human herpes viruses, as EBV infects B lymphocytes and through immortalization process mediated by latent transforming genomic products, confers the infected B cells lymphoblastoid phenotypes. EBV also infects less differentiated or undifferentiated epithelial cells; and it is tightly associated with occurrence of NPC, which is arisen in individuals with normal immune competence. The viral genome is integrated in virtually all tumor cells, and antigenic viral proteins are expressed. It remains therefore, to elucidate the mechanisms of immune evasion in NPC. The viral genomic products may in turn impact on the host cells, released to microenvironment either in free, soluble form or incorporated in exosomes.
EBV encoded LMP1 is recognized as an oncoprotein because of its potential to transform rodent fibroblasts and human lymphocytes. It is also one of then transforming EBV protein that is expressed in EBV associated malignancies. From one third to two thirds EBV positive undifferentiated NPC and a considerable amount of Hodgkin disease, adopting latency II are positive for LMP1. It is a member of Tumor Necrosis Factor (TNF) super family, and has been shown to activate intracellular signal pathways through its interactions with TRAFs, TRADD to induce NFkappaB, MAPK and Akt. LMP1engages intracellular pathways to regulate cell growth and proliferation, including NF-kB and JNK pathways, to induce anti-apoptotic factor Bcl-2, Mcl-1, A20  and A1/Blf1,  has been found to be secreted and localized in exosomal component in culture medium of LMP1 recombinant Baculovirus [50, 51], and the components are likely to inhibition T cell activation .
As an EBV associated B lymphoid tumor, considerable cases of Hodgin's Disease (HD) are positive for LMP1. Exosomes harboring LMP1 are released to enable B cells to gain the capacity to proliferate . LMP1 is actively secreted by Hodgkin-Reed Sternberg (HRS) cells in EBV positive HD cells and direct immunosuppressive properties of LMP1 fragments have been demonstrated .
LMP1, together with another transforming EBV protein BARF1 were expressed in NPC; they have been described to be secreted in the serum and saliva of NPC patients and BARF1 protein and LMP1 complexed with exosome showed powerful mitogenic activity in vitro . Exosomes containing LMP1, when released from EBV infected cells, exert differential effects on the neighboring uninfected cells. A downstream target, ICAM1, an adhesion molecule, ICAM1 is induced by LMP1 in an NFkappaB dependent manner, and contributes to the clumping features of the EBV transformed lymphoblastoid cells. It has been recently reported that LMP1 expressed from cells latently infected with EBV elevates the level of ICAM1 when LMP1 is incorporated in exosomes, and the exosomes are endocytozed by recipient cells .
HLA- class II positive exosomes collected from LMP1 positive and negative NPC xenografts were analyzed. It was found that LMP1 and galectin 9 existed in LMP1 positive cell supernatants, and only galectin 9 in LMP1 negative supernatants. Intrinsic T inhibitory activity by LMP1 was confirmed by the study . Galectin-9 is a ligand of the membrane receptor Tim-3. Its ligation leads to apoptosis in mature Th1 lymphocytes. The incorporation of galectin 9 into exosomes prevents the proteolytic cleavage on it, and maintains its Tim-3 binding activity. The effect inhibits the counteraction of EBVspecific CD4+ cells by the tumor through induction of apoptosis. Such exosomes might play a role in the immune evasion of NPC cells .
MicroRNAs (MiRNAs) are also among composition of exosomes. They are short, non-coding RNAs that are negative posttranscriptional regulator of host gene expression. miRNAs are 19 to 24 nucleotides in length and regulate posttranscriptional gene expression by blocking translation or causing the degradation of target mRNAs [59,60]. These potent gene regulators control up to one third of all genes, affecting such biological functions, including differentiation, cell growth, and disease, especially cancer .
EBV-transformed cells express at least 44 mature viral miRNAs generated from 25 precursors targeting to different viral and cellular genes . Their existence in the serum of EBV infected individuals and the correlation of the serum loads with the intracellular copy number suggested that they exert certain biological effects on recipient cells when released from cells where they are synthesized . The EBV encoded small non-coding miRNAs capable of regulating the expression of the host target genes. The miRNAs can be transferred from an infected cell to uninfected neighboring cells by delivery by exosomes, to down regulate specific target genes. EBV exploits intracellular trafficking and function of miRNA-containing protein complexes to promote or restrict miRNAs sorting into exosomes to perform such regulations .
EBV is the human virus in which the earliest miRNAs were discovered, and it is also the virus with the largest number of miRNA. The 25 pre-miRNAs are matured to 44 miRNAs. The earliest study identified EBV miRNAs clustered in the regions near the mRNA of BHRF1 and the intronic region of the BART . EBERs are the microRNAs encoded by EBV and had been identified before the term of microRNA was proposed. EBERs are abundant RNA in all EBV infected cells, and in the recent years it has been noted that it contributes to the surviving of EBV infected cells by reducing the cellular sensitivity to interferon-induced apoptosis . This activity may explain the genesis of EBV associated tumors in which latency I viral infection is adopted.
The microRNAs, BARTs, BHRF, etc shows a latency dependent expression pattern. BARTs are particularly abundant in the EBVassociated carcinomas and encode a large number of microRNAs (miRNAs). [66, 67] It has been shown Cluster 1 BART miRNAs have been reported to down regulate the expression of the viral LMP1. miR . miRNAs from the BHRF1 region have been associated with replication of the virus and regulation of the chemokine CXCL-11 .
Similar with the host cell dependent protein expression spectrum during EBV latent infection, the expression of EBV encoded miRNAs is also host cell type dependent. During latency III pattern of EBV infection, seen in lymphoblastoid cells in vivo immortalized by EBV, and lymphomas arising in the immune suppressive individuals in vivo, the BHRF1 miRNAs are expressed at high level. The profile, together with the expression of all proteins coded by EBV genome, is due to the EBV transcripts expressed under the control viral promoters Wp or Cp . The cluster of miRNAs are not detectable in cells infected with EBV adopting latency I, e.g. Burkitt lymphoma or latency II, nasopharyngeal carcinoma (NPC) in which an EBV encoded miRNA, BART7 is detected but not in EBV associated lymphomas [71,72,73]. As seen with numerous examples in viral infections, that the invading viruses code for genomic products to counteract the host defense. It has been shown that miRNAs expressed during different types of latent infection modulate the level of host genetic products to support viral parasitism. miR-BHRF1-3, which is highly expressed in type III latency down-regulates interferon-inducible T cell attracting chemokine, CXCL-11/I-TAC . Through blocking the chemokine to activate the chemokine receptor CXCR3 miR-BHRF1-3 inhibit the host interferon response on viral infection.
Products encoded by viral genome have been detected in exosomes released virally infected cells. It is postulated that the exosomal compositions are implicating in the regulation of viral replication as well as the the interactions between the host and the viruses. Among HIV proteins and RNAs in EVs released from HIVinfected cells HIV Transactivation response element (TAR) RNA was detected . TAR is an RNA stem-loop structure located at the 5′ ends of HIV-1 transcripts; it binds Tat, thereby facilitating recruitment of elongation factors and increased production of viral RNA . When transferred via EVs, the population of susceptible target cells was increased by TAR RNA. Exosomes also suppresses HIV infection. When HIV-Nef is incorporated into these exosomes, it competes for the incorporation of CD4 molecules into the vesicles, and decreases the number of CD4, as HIV receptor CD4 to attach to viral particles, thereby decreases the numbers of virions that infect CD4+ T cells .
Exosomes derived from infected cells were found to contain Tax protein and proinflammatory mediators as well as viral mRNA transcripts, including Tax, HBZ, and Env. An exosomes released from HTLV-1-infected Tax-expressing cells contributed to enhanced survival of exosome-recipient cells when treated with Fas antibody. This survival was cFLIP-dependent, with Tax showing induction of NF-κB in exosome-recipient cells. The results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells .
It has long been observed that lesions of tumor are infiltrated by considerable amount of lymphocytes, mostly T cells. The crucial point for mounting efficient antitumor immunity is stimulating the cytotoxicity T response of these infiltrating lymphocytes, to eradicate the malignancies. Mature DC is the most potent APCs for the priming of naive CD8+ T cells. As discussed above, secretion of exosomes incorporated with active immunregulatory factors plays a role in priming T cells response. It has been discovered that DC can secrete MHC class I-bearing exosomes, a possibility exists that exosomes pulsed with synthetic peptides could subserve the DC function consisting in MHC class I-restricted, peptide-specific CTL priming in vitro and in vivo . MHC-I molecules in purified exosomes can be directly loaded with peptide at much greater levels than indirect loading. The direct loading method performed in mildly acidic conditions was effective, and the increase in peptide binding greatly enhanced exosome potency, so the further study the biologic activity of exosomes in vitro was facilitated. Exosomes in Antigen- Presenting Cells (APC), directly loaded with the HLA-A2 restricted tumor peptide stimulated an HLA-A2 specific T-cell line in the tumors. MHC-II molecules, which are abundantly expressed on DC exosomes, were also functionally loaded under the same conditions as MHC-I. This feature allows for delivery of multiple peptide antigens that can stimulate both CD8+ cytotoxic T cells as well CD4+ T helper cells critical for an effective antitumor response. Exosomes loaded with major histocompatibility complex class II/peptide are released by Intestinal epithelial cells have been shown to interact with DCs, strongly inducing activation of T cells . Both peptide- and whole protein-loaded dexosomes induced potent antigen-specific CD8+ T cell activation in vitro, but only protein-loaded dendritic cell derived exosomes (dexosomes) containing both T- and B- cell epitopes induced specific cytotoxic T-lymphocyte (CTL) responses in vivo. In this context, the activation of CD8+ T cells was totally dependent on CD4+ T cells as well as on Marginal Zone B cells (MZBs) .
Tumor associated antigens, including over-expressed oncogene products elicit specific cytotoxic T cell response and can serve as the target of antitumor vaccination. MAGE antigens initially described in melanoma, and the immune responses have been correlated with clinical outcome of melanoma . The antigens are found to express on malignant cells of other tumors like Non-Small Lung Cancer (NSCL) [81,82]. Exosomes pulsed with MHC-I molecule and melanoma specific peptides have been observed to prime T cell response, suggesting that exosome transfers mechanism of functional MHC class I/peptide complexes to DC so as to activate CTL efficiently in vivo . The anticancer therapy using immature autologous DC-derived exosome loaded with peptides derived from such tumor associated antigens with MHC class I and II restriction has entered clinical trial . HLA A2 + NSCLC patients positive for MAGE 3 and 4 were enrolled to the study; their DCs were isolated and DEX was produced, loaded with MAGE 3and 4 derived peptides. The results suggested that T cell response as well as NK lytic activity were augmented . The work is expanding to strategies using many tumor antigens, including immunodominant peptides alone, or peptide pulsed exosomes.
As a nanoscale particle formed by the MVB of the late endosomes, exosomes incorporate biologically active molecules of proteins and miRNA during their biogenesis. They play a role in intercellular communication, exerting influence on such biological events like cell adhesion, motility, as well as immunoregulation. Exosomes also impact on the host virus interactions like entry to permissive cells by viruses, and antiviral immune defense. As rapid and efficient means to transfer macromolecules, exosomes are promising in utilizing in vaccine development and biotherapy against different diseases.
The work in our laboratory is supported by Guangdong Medical Research Fund (2014A276 to XZ) and National Natural Scientific Foundation of China (NSFC) (31170676 to ZH).
Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2: 569–579.
Meckes DG Jr, Raab-Traub N. Microvesicles and viral infection. J Virol. 2011; 85: 12844–12854.
Schwab A, Meyering SS, Lepene B, Iordanskiy S, van Hoek ML, Hakami RM, et al. Extracellular vesicles from infected cells: potential for direct pathogenesis. Front Microbiol. 2015; 6:1132.
Vella LJ, Sharples RA, Nisbet RM, Cappai R, Hill AF. The role of exosomes in the processing of proteins associated with neurodegenerative diseases. Eur Biophys J. 2008; 37: 323–332.
Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, Norman M, et al. Exosomes with immune modulatory features are present in humanbreast milk. J Immunol. 2007; 179: 1969–1978.
Meckes DG Jr, Gunawardena HP, Dekroon RM, Heaton PR, Edwards RH, Ozgur S,Griffith JD, et al. Modulation of B-cell exosome proteins by gammaherpesvirus infection. Proc Natl Acad Sci. 2013; 110: E2925–E2933.
Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, et al. Functional delivery of viral miRNAs via exosomes. Proc. Natl Acad Sci. 2010: 107: 6328–6333.
Testa JS, Apcher GS, Comber JD, Eisenlohr LC. Exosome-driven antigen transfer for MHC class II presentation facilitated by the receptor binding activity of influenza hemagglutinin. J Immunol. 2010; 185: 6608–6616.
Meckes DGJr, Shair KH, Marquitz AR, Kung CP, Edwards RH, Raab-Traub N. Human tumor virus utilizes exosomes for intercellular communication. Proc Natl Acad Sci. 2010; 107: 20370–20375.
Gourzones C, Gelin A, Bombik I, Klibi J, Verillaud B, Guigay J, et al. Extra-cellular release and blood diffusion of BART viral micro-RNAs produced by EBV-infected nasopharyngeal carcinoma cells. Virol J. 2010; 7: e271.
Meckes DG Jr. Exosomal communication goes viral. J Virol. 2015; 89: 5200–5203.
Ridder K, Keller S, Dams M, Rupp AK, Schlaudraff J, Del Turco D, et al. Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation. PLoS Biol. 2014; 12: e1001874.
Zomer A, Maynard C, Verweij FJ, Kamermans A, Schäfer R, Beerling E, et al. In Vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell. 2015; 161: 1046–1057.
Andreu Z, Yanez-Mo M. Tetraspanins in extracellular vesicle formation and function. Front Immunol. 2014; 5: 442.
Segura E, Nicco C, Lombard B, Véron P, Raposo G, Batteux F, et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood. 2005; 106: 216-223.
Nolte-'t Hoen EN, Buschow SI, Anderton SM, Stoorvogel W, Wauben MH. Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood. 2009; 113: 1977–1981.
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015; 527: 329–335.
György B, Szabó TG, Pásztói M, Pál Z, Misják P, Aradi B, et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci. 2011; 68: 2667-2688.
Nolte-'t Hoena E, Tom Cremera T, Gallo RC, Margolis LB. Extracellular vesicles and viruses: Are theyclose relatives? Proc Natl Acad Sci USA. 2016; 113: 9155–9161.
Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen presenting vesicles. J Exp Med. 1996; 183:1161–1172.
Rana S, Zöller M. Exosome target cell selection and the importance of exosomal tetraspanins: a hypothesis. Biochem Soc Trans. 2011; 39: 559-562.
Segura E, Gu´ erin C, Hogg N, Amigorena S, Th´ery C. CD81 dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. J Immunol. 2007; 179: 1489-1496.
Qazi KR, Gehrmann U, Domange Jord¨o E, Karlsson MC, Gabrielsson S. Antigen-loaded exosomes alone induce Th1-type memory through a B-cell-dependent mechanism. Blood. 2009; 113: 2673-2683.
Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, et al. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 2004; 104: 3257-3326.
Denzer K, van Eijk M, Kleijmeer MJ, Jakobson E, de Groot C, Geuze HJ. Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J Immunol. 2000; 165: 1259-1265.
Saunderson SC, Dunn AC, Crocker PR, McLellan AD. CD169 mediates the capture of exosomes in spleen and lymph node. Blood. 2014; 123: 208-216.
Filipazzi P, Bürdek M, Villa A, Rivoltini L, Huber V. Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin Cancer Biol. 2012; 22: 342-349.
Johansson SM, Admyre C, Scheynius A, Gabrielsson S. Different types of in vitro generated human monocyte-derived dendritic cells release exosomes with distinct phenotypes. Immunology. 2008; 123: 491-499.
Admyre C, Johansson SM, Qazi KR, Filén JJ, Lahesmaa R, Norman M, et al. J Immunol. 2007; 179: 1969-1978.
Yang C, Ruffner MA, Kim SH, Robbins PD. Plasma-derived MHC class II+ exosomes from tumor-bearing mice suppress tumor antigen-specific immune responses. Eur J Immunol. 2012; 42: 1778-1784.
Yang C, Robbins PD. Immunosuppressive exosomes: a new approach for treating arthritis. Int J Rheumatol. 2012; 2012: 573528.
Cai Z, Fei Yang F, Yu L, Yu Z, Jiang L, Wang Q, et al. Invasion via Fas Signaling Pathway Activated T Cell Exosomes Promote Tumor. J Immunol. 2012; 188: 5954-5961.
Mattheolabakis G, Aldawsari H, and Amiji M. Exosomes as nano carriers for immunotherapy of cancers and inflammatory diseases. Clin Immunol. 2015; 160: 46–58.
MacDonaldI, Kuehn MJ. Offense and defense: microbialmembrane vesicles play both ways. Res Microbiol. 2012; 163, 607–618.
Gehrmann U, Näslund TI, Hiltbrunner S, Larssen P, Gabrielsson S. Harnessing the exosome-induced immune response for cancer immunotherapy. Semin Cancer Biol. 2014; 28: 58–67.
Xie Y, Haifeng Zhang, Wei Li, Yulin Deng, Manjunatha AM, Rajni Chibbar, et al. Dendritic Cells Recruit T Cell Exosomes via Fas Ligand-Mediated Cytotoxicity Downregulation of Peptide/MHC Class I and CD8+ CTL Responses through Exosomal LFA-1 Leading to Inhibition of J Immunol. 2010; 185: 5268-5278.
Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009; 9: 581–593.
Schorey JS, Bhatnagar S. Exosome function: from tumor immunology to pathogen biology. Traffic. 2008; 9: 871–881.
Lugini L, Cecchetti S, Huber V, Luciani F, Macchia G, Spadaro F, et al. Immune Surveillance Properties of Human NK Cell-Derived Exosomes. J Immunol. 2012; 189: 2833-2842.
Mincheva-Nilsson L, Baranov V. Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Semin Cancer Biol. 2014; 28: 24-30.
Iizasa H, Wulff BE, Alla NR, Maragkakis M, Megraw M, Hatzigeorgiou A, et al. Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency. J Biol Chem. 2010; 285: 33358-33370.
Zhang G, Zong J, Lin S, Verhoeven RJ, Tong S, Chen, et al. Circulating Epstein-Barr virus microRNAs miR-BART7 and miR-BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment. Int J Cancer. 2015; 136: E301-312.
Marquitz AR, Mathur A, Chugh PE, Dittmer DP, Raab-Traub N. Expression profile of microRNAs in Epstein-Barr virus-infected AGS gastric carcinoma cells. J Virol. 2014; 88: 1389-1393.
Shinozaki-Ushiku A, Kunita A, Isogai M, Hibiya T, Ushiku T, Takada K, et al. Profiling of Virus-Encoded MicroRNAs in Epstein-Barr Virus-Associated Gastric Carcinoma and Their Roles in Gastric Carcinogenesis. J Virol. 2015; 89: 5581-5591.
Xing L, Kieff E. Epstein-Barr virus BHRF1 micro- and stable RNAs during latency III and after induction of replication. J Virol. 2007; 81: 9967-9975.
Rowe M, Peng-Pilon M, Huen DS, Hardy R, Croom-Carter D, Lundgren E, et al. Upregulation of bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell-specific response that is delayed relative to NF-kappa B activation and to induction of cell surface markers. J Virol. 1994; 68: 5602-5612.
Wang S, Rowe M, Lundgren E. Expression of the Epstein Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines. Cancer Res. 1996; 56: 4610-4613.
Laherty CD, Hu HM, Opipari AW, Wang F, Dixit VM. The Epstein-Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor kappa B. J Biol Chem. 1992; 267: 24157-24160.
D'Souza B, Rowe M, Walls D. The bfl-1 gene is transcriptionally upregulated by the Epstein-Barr virus LMP1, and its expression promotes the survival of a Burkitt's lymphoma cell line. J Virol. 2000; 74: 6652-6658.
Flanagan J, Middeldorp J, Sculley T. Localization of the Epstein-Barr virus protein LMP 1 to exosomes. J Gen Virol. 2003; 84: 1871-1879.
Vazirabadi G, Geiger TR, CoffinWFI II, Martin JM. Links Epstein-Barr virus latent membrane protein-1(LMP-1) and lytic LMP-1localization in plasma membrane-derived extracellular vesicles and intracellular virions. J Gen Virol. 2003; 84: 1997-2008.
Gutzeit C, Nagy N, Gentile M, Lyberg K, Gumz J, Vallhov H, et al. Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells. J Immunol. 2014; 192: 5852-5862.
Houali K, Wang X, Shimizu Y, Djennaoui D, Nicholls J, Fiorini S, et al. A New Diagnostic Marker for Secreted Epstein-Barr Virus Encoded LMP1 and BARF1 Oncoproteins in the Serum and Saliva of Patients With Nasopharyngeal Carcinoma. Clin Cancer Res. 2007; 13: 4993-5000.
Nanbo A, Kawanishi E, Yoshida R, Yoshiyama H. Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. J Virol. 2013; 87: 10334-10347.
Keryer-Bibens C, Pioche-Durieu C, Villemant C, Souquère S, Nishi N, Hirashima M, et al. Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral latent membrane protein 1 and the immunomodulatory protein galectin 9. BMC Cancer. 2006; 6: 283.
Klibi J, Niki T, Riedel A, Pioche-Durieu C, Souquere S, Rubinstein E, et al. Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood. 2009; 113: 1957-1966.
Pegtel DM, van de Garde, Middeldorp JM. Viral miRNAs exploiting the endosomal-exosomal pathway for intercellular cross-talk and immune evasion. Biochim Biophys Acta. 2011; 1809: 715-721.
Cullen BR. Viruses and microRNAs. Nat Genet. 2006; 38: S25-S30.
Garofalo MG, Condorelli, Croce CM. MicroRNAs in diseases and drug response. Curr Opin Pharmacol. 2008; 8: 661-667.
Barth S, Meister G, Grässer FA. EBV-encoded miRNAs. Biochim Biophys Acta. 2011; 1809: 631-640.
Wong AM, Kong KL, Tsang JW, Kwong DL, Guan XY. Profiling of Epstein-Barr virus-encoded microRNAs in nasopharyngeal carcinoma reveals potential biomarkers and oncomirs. Cancer. 2012; 118: 698-710.
Forte, Luftig MA. The role of microRNAs in Epstein-Barr virus latency and lytic reactivation. Microbes and Infection. 2011; 13: 1156-1167.
Filipowicz W, S N Bhattacharyya, N Sonenberg. Mechanisms of posttranscriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008; 9: 102-114.
Pfeffer S, Zavolan M, Grässer FA, Chien M, Russo JJ, Ju J, et al. Identification of virus-encoded microRNAs. Science. 2004; 304: 734-736.
Chen HL, Lung MM, Sham JS, Choy DT, Griffin BE, Ng MH. Transcription of BamHI-A region of the EBV genome in NPC tissues and B cells. Virology. 1992; 191:193-201.
Smith PR, de Jesus O, Turner D, Hollyoake M, Karstegl CE, Griffin BE, et al. Structure and coding content of CST (BART) family RNAs of Epstein-Barr virus. J Virol. 2000; 74: 3082-3092.
Lo AK, To KF, Lo KW, Lung RW, HuiJW, Liao G, et al. Modulation of LMP1 protein expression by EBV-encoded microRNAs. Proc Natl Acad Sci USA. 2007; 104, 16164-16169.
Xia T, O'Hara A, Araujo I, Barreto J, Carvalho E, Sapucaia JB, et al. EBV microRNAs in primary lymphomas and targeting of CXCL-11 by ebv-mir-BHRF1-3. Cancer Res. 2008; 68: 1436-1442.
Zhu JY, Pfuhl T, Motsch N, Barth S, Nicholls J, Grässer F, et al. Identification of novel Epstein-Barr virus microRNA genes from nasopharyngeal carcinomas. J Virol. 2009; 83: 3333-3341.
Cosmopoulos K, Pegtel M, Hawkins J, Moffett H, Novina C, Middeldorp J, et al. Comprehensive profiling of Epstein-Barr virus microRNAs in nasopharyngeal carcinoma. J Virol. 2009; 83: 2357-2367.
Chan JY, Gao W, Ho WK, Wei WI, Wong TS. Overexpression of Epstein-Barr virus-encoded microRNA-BART7 in undifferentiated nasopharyngeal carcinoma. Anticancer Res. 2012; 32: 3201-3210.
He N. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1transcription. Mol Cell. 2010; 38: 428–438.
de Carvalho JV, de Castro RO, da Silva EZ, Silveira PP, Arruda E, Jamur MC. Nef neutralizes the ability of exosomes from CD4+ T cells to act as decoys during HIV-1 infection. PLoS One. 2014; 9: e113691.
Ali SA, Huang MB, Campbell PE, Roth WW, Campbell T, Khan M, et al. Genetic characterization of HIV type 1 Nef-induced vesicle secretion. AIDS Res Hum Retrovir. 2010; 26: 173–192.
Jaworski E, Narayanan A, Van Duyne R, Shabbeer-Meyering S, Iordanskiy S, Saifuddin M, et al. Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein. J Biol Chem. 2014; 289: 22284-22305.
Hsu DH, Paz P, Villaflor G, Rivas A, Mehta-Damani A, Angevin, E, et al. Exosomes as a tumor vaccine: enhancing potency through direct loading of antigenic peptides. J. Immunother. 2003; 26: 440-450.
Mallegol J, Van Niel G, Lebreton C, Lepelletier Y, Candalh C, Dugave C, et al. T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology. 2007; 132: 1866-1876.
Näslund TI, Gehrmann U, Gabrielsson S. Cancer immunotherapy with exosomes requires B-cell activation. Oncoimmunology. 2013; 2: e24533.
Reynolds SR, Zeleniuch-Jacquotte A, Shapiro RL, Roses DF, Harris MN, Johnston D, et al. Vaccine-induced CD8+ T-cell responses to MAGE-3 correlate with clinical outcome in patients with melanoma. Clin Cancer Res. 2003; 9: 657-662.
Gotoh K, Yatabe Y, Sugiura T, Takagi K, Ogawa M, Takahashi T, et al. Frequency of MAGE-3 gene expression in HLA-A2 positive patients with non-small cell lung cancer. Lung Cancer. 1998; 20: 117-125.
Park JW, Kwon TK, Kim IH, Sohn SS, Kim YS, Kim CI, et al. A new strategy for the diagnosis of MAGE-expressing cancers. J Immunol Methods. 2002; 266: 79-86.
André F, Chaput N, Schartz NE, Flament C, Aubert N, Bernard J, et al. Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol. 2004; 172: 2126-2136.
Escudier B, Dorval T, Chaput N, André F, Caby MP, Novault S, et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med. 2005; 3: 10.
Morse MA, Garst J, Osada T, Khan S, Hobeika A, Clay TM, et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med. 2005; 3: 9.


text:
The Relationship between Academic Abilities and Internal/External Thinking Styles on Digital Game Flow Experience
I Hua Chen, Ya-Ting C Yang, Wan-Chi Wu, Wei-Chun Chiang, National Cheng Kung University, Taiwan
E-Learn: World Conference on E-Learning in Corporate, Government, Healthcare, and Higher Education, Oct 09, 2012 in Montréal, Quebec, Canada ISBN 978-1-880094-98-3 Publisher: Association for the Advancement of Computing in Education (AACE), San Diego, CA
"Flow" is referred to as a mental state of optimal experience resulted from full immersion. Recent studies on digital game based learning have applied the flow theory to explain the immersion of students in game playing. However, the relationship between students' attributes (e.g., students' thinking styles and academic abilities) and flow experience has been neglected. This study tried to investigate: (a) the relationship between internal/external thinking styles and flow experience; (b)The moderation effect of academic abilities on the relationship between internal/external thinking styles and flow experience ; (c)The relationship between flow experience and subsequent academic performance. The results showed that: (a) Internal/external thinking styles were significant positive related with digital game flow experience. (b) Students' academic abilities moderated the relationship between internal/external thinking styles and digital game flow experience.(c) Digital game flow experience was not significant related with the subsequent academic performance.
Chen, I.H., Yang, Y.T.C., Wu, W.C. & Chiang, W.C. (2012). The Relationship between Academic Abilities and Internal/External Thinking Styles on Digital Game Flow Experience. In T. Bastiaens & G. Marks (Eds.), Proceedings of E-Learn 2012--World Conference on E-Learning in Corporate, Government, Healthcare, and Higher Education 1 (pp. 911-918). Montréal, Quebec, Canada: Association for the Advancement of Computing in Education (AACE). Retrieved January 18, 2020 from https://www.learntechlib.org/primary/p/41712/.
Annetta, L.A., Minogue, J., Holmes, S.Y., & Cheng, M.T. (2009). Investigating the impact of videogames on high school students' engagement and learning about genetics. Computers& Education, 53(1), 74-85.
Cheng, I.-T. (2007). The Relationship between Academic Emotions and Academic Achievement of Junior High School Students (Unpublished master's thesis). National Cheng Kung University Institution of Education, Taiwan.
Chuang, T.Y., & Chen, W.F. (2009). Effect of Computer-Based VideoGames on Children: An Experimental Study. Educational Technology& Society, 12(2), 1-10.
Csikszentmihalyi, M. (1990). Flow: The psychology of optimal experience. New York: Harper& Row.
Csikszentmihalyi, M. (1997). Creativity: flow and the psychology of discovery and invention: New York: Harper.
Ebner, M., & Holzinger, A. (2007). Successful implementation of user-centered game based learning in higher education: An example from civil engineering. Computers& Education, 49(3), 873-890.
Eccles, J.S., & Wigfield, A. (2002). Motivation Beliefs Values and Goals. Annual Review of Psychology 53, 109-132.
Fu, F.-L., Su, R.-C., & Yu, S.-C. (2009). EGameFlow: A scale to measure learners' enjoyment of e-learning games. Computers& Education, 52, 101-112.
Huang, W.H., Huang, W.Y., & Tschopp, J. (2010). Sustaining iterative game playing processes in DGBL: The relationship between motivational processing and outcome processing. Computers& Education, 55(2), 789-797.
Inal, Y., & Cagiltay, K. (2007). Flow experiences of children in an interactive social game environment. British Journal of Educational Technology, 38(3), 455-464.
Jackson, S., & Eklund, R. (2004). The Flow Scales Manual. Morgantown, WV: Fitness Information-917-Technology.
Jackson, S., Ford, S., Kimiecik, J., & Marsh, H. (1998). Psychological Correlates of Flow in Sport. Journal of Sport& Exercise Psychology 20, 358-378.
Jin, S.A.A. (2011). "I Feel Present. Therefore, I Experience Flow": A Structural Equation Modeling Approach to Flow and Presence in VideoGames. Journal of Broadcasting& Electronic Media, 55(1), 114-136.
Keller, J., & Bless, H. (2008). Flow and regulatory compatibility: An experimental approach to the flow model of intrinsic motivation. Personality and Social Psychology Bulletin, 34(2), 196-209.
Kiili, K. (2005). Digital game-based learning: Towards an experiential gaming model. Internet and Higher Education, 8, 13-24.
Kim, B., Park, H., & Baek, Y. (2009). Not just fun, but serious strategies: Using meta-cognitive strategies in game-based learning. Computers& Education, 52, 800-810.
Li, Q. (2010). Digital game building: learning in a participatory culture. Educational Research, 52(4), 427-443.
Liu, E.Z.F. (2011). AVOIDING INTERNET ADDICTION WHEN INTEGRATING DIGITAL GAMES INTO TEACHING. Social Behavior and Personality, 39(10), 1325-1335.
Nacke, L.E., Grimshaw, M.N., & Lindley, C.A. (2010). More than a feeling: Measurement of sonic user experience and psychophysiology in a first-person shooter game. Interacting with Computers, 22, 336-343.
Nacke, L., & Lindley, C.A. (2009). Affective Ludology, Flow and Immersion in a First-Person Shooter: Measurement of Player Experience. Loading…, 3(5).
Prensky, M. (2001). Digital game-based learning. New York: McGraw-Hill.
Sedig, K. (2007). Toward operationalization of 'flow' in mathematics learnware. Computers in Human Behavior, 23, 2064-2092.
Sharma, S., Durand, R.M., & Gur-Arie, O. (1981). Identification and Analysis of Moderator Variables. Journal of Marketing Research, 18(3), 291-300.
Skadberga, Y.X., & Kimmelb, J.R. (2004). Visitors' flow experience while browsing a Website: its measurement, contributing factors and consequences. Computers in Human Behavior, 20, 403-422.
Smith, B.P. (2006). Flow and the enjoyment of videogames. PHD, THE UNIVERSITY OF ALABAMA.
Sternberg, R.J. (1994). Allowing for Thinking Styles. Educational Leadership, 52(3), 36-40.
Sweetser, P., & Wyeth, P. (2005). GameFlow: A Model for Evaluating Player Enjoyment in Games. ACM Computers in Entertainment, 3(3), 1-23.
Wang, S.-H. (2009). The Research of Correlation among Cultural Capital, Matacognition and Academic Effects: A case study of sixth graders in elementary schools in Tainan County (Unpublished master's thesis). National Tainan University Graduate Institute of Educational Entrepreneurship and Management, Taiwan. Zhang, L.-F. (2000). Relationship between Thinking Styles Inventory and Study Process Questionnaire. Personality and Individual Differences, 29, 841-856.
These references have been extracted automatically and may have some errors. Signed in users can suggest corrections to these mistakes.
Suggest Corrections to References
Integrating Educational Technology into the Secondary Science Teaching
Increasing Teacher Efficacy throughTechnology-Based Professional Development
Patterns of Participation in Online Asynchronous Discussions
Does perceived importance of reflection influences the extent of in-depth...
The Layers of Authenticity: Designing for Learner Experience
Design, Development, and Evaluation of an e-Learning Module User Interface
Interactivity and Aesthetics: Towards an Information Visualization Framework ...
College Teachers' Social Representations of Pedagogical Mediation and the...
Study on designing platform for the cultural connectivity in a society -with...
Editorial: AECT – SITE Collaboration Through the National Technology...
Blog Modul 1

redpajama_set_name: RedPajamaCommonCrawl


text:
\section{Introduction}
AU~Mic is a nearby \citep[$9.91\pm 0.10$~pc,][]{van07} M1Ve flare star
\citep{tor06} with the young age of $12^{+8}_{-4}$~Myr \citep{zuc01}, a key
epoch in the formation of planetary systems. The star is surrounded by a nearly
edge-on circumstellar disk discovered in coronographic images of scattered
starlight that extends to a radius of at least 210~AU \citep{kal04}. Since the
small grains responsible for scattering should be removed rapidly by stellar
pressure forces, the disk is thought to consist of the collisional debris of
unseen planetesimals experiencing ongoing impacts \citep[for recent reviews of
the debris disk phenomenon, see][]{wya08,kri10}. Because of its proximity, the
AU~Mic debris disk has become one of the best studied examples at optical and
infrared wavelengths, including detailed imagery of both intensity and
polarization from the {\em Hubble Space Telescope} \citep{kri05,gra07}.

Many observational properties of the AU~Mic debris disk bear striking
similarities to the archetype debris disk surrounding $\beta$~Pic, also viewed
nearly edge-on and located in the same young moving group. In particular, the
midplane optical surface brightness profiles of these disks are remarkably
alike, with shallow inner slopes ($\sim 1/r^{1-2}$) that steepen substantially
($\sim 1/r^{4-5}$) in the outer regions, near 35~AU and 100~AU for AU~Mic and
$\beta$~Pic, respectively \citep{kri05,fit07,hea00,gol06}. These similarities
inspired the development of a unified framework for debris disks based on a
localized belt of planetesimals, or ``birth ring'', that produces dust in a
collisional cascade \citep{str06,aug06}. The smallest grains are blown out from
the belt by radiation and winds from the star, larger grains are launched into
eccentric orbits with the same periastron as the belt, and the largest grains,
which are minimally affected by non-gravitational forces, do not travel far
from the belt before being ground down. The grains are therefore segregated
according to their size, which gives rise to the characteristic scattered light
profile. For these dynamics to prevail, the disks must be substantially free of
gas \citep{the05}, a property confirmed by measurements at ultraviolet
wavelengths \citep{rob05,fra07}.

A ``birth ring'', if present, would remain hidden in optical and infrared
images dominated by small grains that populate an extended halo
\citep[e.g.,][]{su05}. By contrast, observations at (sub)millimeter wavelengths
highlight thermal emission from the largest grains and hence the location of
the dust-producing planetesimals \citep{wya06}. To date, the best case for a
``birth ring'' comes from millimeter observations of $\beta$~Pic \citep{wil11}.
While the optical disk of $\beta$~Pic extends more than $1000$~AU from the
star, the millimeter imaging reveals a much more compact belt of emission at
$\sim95$~AU radius. This millimeter emission belt coincides with the change in
the slope of the optical surface brightness, which in the models marks the
outer extent of the colliding planetesimals.

Previous (sub)millimeter-wave observations of AU Mic did not have sufficient
angular resolution to reveal much about the emission morphology. A detection at
850~$\mu$m using JCMT/SCUBA ($14''$ beam) indicated a reservoir of cold dust
with mass $\sim0.01$~M$_{\oplus}$, but did not resolve any structure
\citep{liu04b}. Subsequent observations at 350~$\mu$m using CSO/SHARC~II
($10''$ beam) marginally resolved an orientation compatible with the scattered
light, but were otherwise limited \citep{che05}. In this {\em Letter}, we
present imaging observations of AU Mic at 1.3~millimeters using the
Submillimeter Array (SMA)\footnote{The Submillimeter Array is a joint project
between the Smithsonian Astrophysical Observatory and the Academica Sinica
Institute of Astronomy and Astrophysics and is funded by the Smithsonian
Institution and the Academica Sinica.} that obtain $3''$ resolution and provide
evidence for a planetesimal belt.

\section{Observations} \label{sec:obs}
We observed AU~Mic with the SMA \citep{ho04} on Mauna Kea, Hawaii at
1.3~millimeters wavelength using the compact and extended configurations of the
array. Table~\ref{tab:obs} provides basic information about these observations,
including the observing dates, baseline lengths, and atmospheric opacities. The
weather conditions were good for all of these observations and best for the two
compact configuration tracks when only 6 of the 8 array antennas were
available. The phase center was $\alpha = 20^h45^m09\fs53$, $\delta =
-31\degr20\arcmin27\farcs2$ (J2000), offset by $\sim5\farcs3$ from the location
of the star. The $\sim54''$ (FWHM) field of view is set by the primary beam
size of the 6~meter diameter array antennas. The total bandwidth available was
8~GHz derived from two sidebands spanning $\pm4$~to~$8$~GHz from the LO
frequency. Time dependent complex gains were calibrated using observations of
two quasars, J2101-295 (3.9 degrees away) and J1924-292 (17.4 degrees away),
interleaved with observations of AU Mic in a 15~minute cycle. The passband
shape for each track was calibrated using available bright sources, mainly
J1924-292. The absolute flux scale was set with an accuracy of $\sim10\%$ using
observations of Callisto or Ganymede in each track. All of the calibration
steps were performed using the IDL based MIR software, and imaging and
deconvolution were done with standard routines in the MIRIAD package. We made a
series of images with a wide range of visibility weighting schemes to explore
compromises between higher angular resolution and better surface brightness
sensitivity.

\begin{deluxetable}{lcccc}
\tablecaption{
Submillimeter Array Observations of AU Mic
\label{tab:obs}
}
\tablewidth{0pt}
\tablehead{
\colhead{Observation} & \colhead{2011 Jul 31} & \colhead{2011 Sep 26} &
                      \colhead{2011 Sep 27} & \colhead{2011 Oct 25}
}
\startdata
Array Configuration & Extended & Compact & Compact & Compact \\
Number of Antennas & 8 & 6 & 6 & 7 \\
Baseline Lengths (m) & 10--189 & 8--68 & 8--68 & 8--68 \\
LO frequency (GHz) & 235.6 & 225.4 & 225.4 & 235.6 \\
225 GHz atm. opacity\tablenotemark{a} & 0.10  & 0.10--0.06 & 0.06 & 0.08 \\
\enddata
\tablenotetext{a}{Measured at the nearby Caltech Submillimeter Observatory.}
\end{deluxetable}

\section{Results and Analysis} \label{sec:result}
\subsection{1.3 Millimeter Emission} \label{sec:continuum}
Figure~\ref{fig:image} shows a contour image of the 1.3~millimeter emission
overlaid on a {\it Hubble Space Telescope}/ACS coronographic image of optical
scattered light (F606W filter) from \citet{gra07}. The synthesized beam size
for this 1.3~millimeter image is $3\farcs3 \times 2\farcs6$ ($33\times26$~AU),
position angle $-12{\degr}$, obtained with natural weighting and an elliptical
Gaussian taper $1\farcs5 \times 1\farcs0$ (FWHM) oriented east-west to make the
beam shape more circular. The rms noise in this image is 0.40~mJy~beam$^{-1}$,
and the individual peaks have a signal-to-noise $\gtrsim7$. The star symbol
marks the stellar position corrected for proper motion, offset by $(3\farcs20,
-4\farcs25)$ from the phase center. The image shows a resolved band of 1.3
millimeter emission that extends approximately symmetrically from the stellar
position to the southeast and northwest. By fitting a line to the positions of
the two peaks in the image, we estimate the position angle of the emission
structure to be $130\pm 2\degr$, in excellent agreement with the disk
orientation inferred from scattered light observations \citep{liu04a}. From its
position angle and double peaked morphology, we identify the emission structure
as a limb-brightened dust belt. Note that thermal emission from the stellar
photosphere contributes only $0.06$~mJy at this wavelength, and even the
strongest synchrotron radio flares from stellar activity should remain well
below the noise \citep{kun87}. The total flux density obtained by integrating
over a box that surrounds the emission is $8.5\pm2$~mJy, where the uncertainty
is estimated conservatively by evaluating boxes of the same size in
emission-free regions of the image. No other significant features are detected
in the field of view.

An extrapolation of the measurements at shorter wavelengths indicates that
missing flux due to the spatial filtering by the SMA is not a significant issue
for these observations. The spectral index between 350~$\mu$m
\citep{che05} and 850~$\mu$m
\citep{liu04b} is $1.7^{+0.3}_{-0.5}$, which predicts
$7.1^{+2.0}_{-1.2}$~mJy at 1.3~millimeters, in good agreement with the SMA
measurement. This shallow index is consistent, within the uncertainties, with
values near 2.0 determined for a sample of debris disks by \citet{gas11},
notably for stars later than F-type where dust temperatures are so low that the
Rayleigh-Jeans approximation in this part of the spectrum is invalid.  We
conclude that the compact structure detected by the SMA accounts for all of the
1.3~millimeter emission in the AU~Mic system.

\subsection{A Simple Disk Model} \label{sec:models}
To characterize the millimeter emission structure, we use a simple parametric
disk model, following closely the method used by \citet{wil11} for analyzing
similar observations of the $\beta$~Pic disk. We assume the emission arises
from a geometrically thin, axisymmetric belt with a radial surface brightness
profile given by $I\propto f(r)r^{-q}$. This functional form is intended to
capture the essence of low optical depth emission from a disk with a spatially
invariant dust emissivity, surface density profile $f(r)$, and temperature
profile that falls off with radius as a power-law. We fix the power-law index
$q=0.5$ to approximate radiative heating from the central star, and we consider
two shapes for $f(r)$: (1) an annulus with power law slope, $f(r) \propto
r^{-p}$ for $R \pm \Delta R/2$, $p \in {0,1}$, and (2) a Gaussian, $f(r)
\propto \exp{[-((r-R)/ \sqrt{2} \Delta R)^2]}$. In each case, the model is
described by three parameters: a center radius $R$, width $\Delta R$, and total
flux density $F = \int I d\Omega$. We fix the disk inclination at $89\fdg5$ and
position angle at $130\degr$, as determined from scattered light data
\citep{kri05}, and place the origin within $0\farcs1$ of the nominal stellar
position (within the SMA astrometric accuracy). Note that the vertical
thickness of the millimeter grain population is expected to be $<0\farcs25$
\citep{the09}, negligible compared to the resolution of the data. The utility
of this simple modeling approach is to provide basic constraints while avoiding
the multitudinous assumptions about grain properties, dynamics, and radiative
transfer required in more sophisticated treatments.

To estimate the model parameters and their uncertainties, we calculate
three-dimensional grids spanning appropriate ranges of the parameter values.
For the Gaussian model, the grid covers $20 < R < 47$~AU and $1 < \Delta R <
40$~AU in 1~AU steps, and $5 < F < 11$~mJy in 0.2~mJy steps.  For each position
in a model grid, we compute a set of synthetic SMA visibilities and compare
directly to the data with a $\chi^2$ value (the sum of real and imaginary
components over all spatial frequencies) that uses natural weights modified by
the Gaussian taper used for the image in Figure~\ref{fig:image}. The rightmost
panel of Figure~\ref{fig:model} shows the $\chi^2$ surface in the $(R,\Delta
R)$ plane for the Gaussian model after marginalizing over $F$. The best-fit
model is marked by a cross, and the contours delineate (marginalized) $1
\sigma$ intervals in $\Delta \chi^2$. The best-fit center radius is $R =
36^{+7}_{-16}$~AU, with corresponding width $\Delta R = 10^{+13}_{-8}$~AU (or
FWHM = $2\sqrt{2\ln2} \Delta R = 23^{+31}_{-19}$~AU) and flux density $F = 8.0
\pm 1.2$~mJy. The three lefthand panels of Figure~\ref{fig:model} show the
original 1.3~millimeter image from Figure~\ref{fig:image}, the Gaussian model
image obtained using the best-fit parameter values and the same visibility
weighting scheme, and the imaged residuals (where data$-$model subtraction is
conducted on the visibilities).  This comparison shows clearly that the
best-fit model reproduces the main features of the image and leaves no
systematic residuals. The power-law models for $f(r)$ give similar best-fit
parameter values: for $p=0$, we find $R=35\pm6$~AU and $\Delta R =
38^{+26}_{-18}$~AU (where the upper limit is set by the computational grid
boundary). For $p=1$, the best-fit locus is shifted to roughly $10\%$ larger
values of $R$, a manifestation of the degeneracy between the radial gradient
and emission extent. All of these best-fit models reproduce the observed SMA
visibilities equally well (i.e., have effectively the same minimum $\chi^2$
values).

The modest signal-to-noise of the observations preclude placing tighter
constraints on the model parameters. Nonetheless, it is reassuring that
consistent results are obtained from the various assumptions about the emission
morphology. Each gives a similar center radius, as well as an effectively
cleared central cavity with size compatible with that inferred from scattered
light \citep[$\sim12$~AU][]{kri05} and the lack of mid-infrared emission
\citep[$\sim17$~AU][]{liu04b}. The best-fit Gaussian model reproduces better
the contrast of the maxima to the extended emission of the disk in the image
plane, but there is no clear preference for any of the functional forms. Of
course, none of these {\em ad hoc} models are perfect, and more sensitive data
will be needed to constrain further the details of the emission distribution.

\section{Discussion} \label{sec:discussion}
We have spatially resolved the thermal emission at 1.3 millimeters from the
AU~Mic debris disk, thereby revealing the distribution of its millimeter grain
population. These large grains are expected to have dynamics similar to the
unseen dust-producing planetesimals, and the emission at this long wavelength
provides a direct link to their spatial distribution.

The overall structure of the AU~Mic millimeter emission is reproduced well by a
belt surrounding the star centered near a radius of $35$~AU. The inferred
location of this emission belt coincides with the region over which the
scattered light brightness profile of the disk steepens markedly, the feature
that provided impetus for developing the ``birth ring'' model. Like AU~Mic's
more massive sister star $\beta$~Pic \citep{wil11}, the resolved
multi-wavelength data are consistent with a scenario where destructive
collisions of planetesimals within the belt create grains with a spectrum of
sizes, and the effects of size-dependent dust dynamics generate the millimeter
emission and spatially extended scattered light nebula. For $\beta$~Pic, the
intense stellar radiation pressure can account for the large halo of small
grains in the outer disk.  But for AU~Mic, which is about two orders of
magnitude less luminous, the much weaker stellar radiation field is apparently
augmented by a stellar wind to expel small grains \citep{str06,aug06}.

Though the fractional radial extent of the AU~Mic millimeter emission is not
strongly constrained, the best-fit models suggest that it could be broad,
$\Delta R/R \sim 1$. For $\beta$~Pic, the millimeter emission is characterized
by $\Delta R/R < 0.5$, with the upper end favored for the width of the
underlying dust-producing planetesimal belt from detailed models of the knee of
the scattered light profile \citep{hah10}. Such broad belts are not unusual
features of debris disks, in particular among the few resolved at millimeter
wavelengths \citep{hug11}. An inner cavity devoid of dust is plausibly
maintained by the combination of grinding collisions in the belt and clearing
by stellar radiation forces, though a tenable alternative is that the inner
regions are swept clear by a planet. Planets seem to be the most viable
explanation for the millimeter cavities common to the gas-rich transition disks
around younger, pre-main-sequence stars \citep{and11}. While a planet has been
imaged to orbit within the cavity in the disk around $\beta$~Pic \citep{lag10},
direct evidence for planets in the AU Mic system remains elusive, both from
high contrast imaging observations \citep{mas05,met05} and from transit
searches \citep{heb07}. The outer boundary of the emission belts may reflect
the outer extent of successful planetesimal formation, or it may simply
mark the edge of the region where the planetesimal stirring mechanism has
been successful at initiating dust-producing collisions, as in the models of
\citet{ken04}.

These new millimeter observations of AU~Mic show the global structure of large
grains in its debris disk, but they do not have sufficient resolution and
sensitivity to reveal any significant departures from axisymmetry or
substructure that might result from gravitational interactions with unseen
planets. The higher resolution images of scattered light clearly show several
radial and vertical inhomogeneities at subarcsecond scales \citep[features A-E,
see][]{liu04a,met05,fit07}. If these substructures have counterparts at
millimeter wavelengths, then future observations with the Atacama Large
Millimeter/Submillimeter Array (ALMA) may be able to detect them, pinpoint the
location of parent bodies, and constrain their origins.

\acknowledgments{
We thank James Graham for providing the {\it Hubble Space Telescope} image in
Figure 1.  A. M. H. is supported by a fellowship from the Miller Institute for
Basic Research in Science.
}

{\it Facility:} \facility{Submillimeter Array}

redpajama_set_name: RedPajamaArXiv


I live on a quiet road in the heart of the Napa Valley, surrounded by vineyards. My yard is bright green with all this winter rain and the recently pruned vineyards are clean, crisp and beautiful. The view is stunning. Though, I came home one day last week to bright yellow stripes throughout the vineyards – a sure sign that Round-up was sprayed to control weed growth at the base of the vines. I couldn't help but feel disappointment and concern. Is the air and the dirt contaminated? Will these chemicals reach our drinking water? Will I track these pesticides into my home on the soles of my shoes?
Prior to my time at Clif Family Winery, I had never worked with organically farmed grapes. There was always an interest, but the added costs and associated risks to the crop were inhibiting factors. When I joined the Clif team, I was interested and exited to begin to understand what it meant to farm grapes organically. (All three of the Clif Family Winery Estate vineyards, as well as the Farm, are CCOF certified.) With one season under my belt, I have a much broader perspective on the topic and a fond appreciation for these sustainable practices.
What does it mean to farm organically? In the most simple terms, our grapes are grown on soils that are free of prohibited substances, such as synthetic pesticides, ensuring our fruit is not contaminated. In the vineyard, we use only CCOF approved applications for mildew control, we dig up weeds rather than kill them with chemicals, and we release predatory mites to control damaging mite populations. These practices do cost more, due to higher priced products and labor intensive processes. The results – our dirt and grapes will be free of toxic pesticides, keeping you, our farm workers and our neighbors healthy.
So, after a year of working under these new, healthier and more environmentally friendly conditions, I am now a huge proponent of organic farming and organic eating. At the grocery store, I will now choose the $6 box of organic raspberries over the $4 box of non-organic. And, when I look out the window at the conventionally farmed vineyards that surround me, I know that as a community, we can do better.


Manitoba Employment Equity Practitioners Association (MEEPA) is non-profit association of professionals working together to achieve equitable and diverse workplaces. About 50 members and guests attended the November 29, 2013 session on Aboriginal employment practices and opportunities. Speakers included Minister Kevin Chief, Shaun Loney (BUILD and Aki Energy) and myself speaking about employment practices at Inner City Renovation.
A review of my book "Inner City Renovation- How a Social Enterprise Changes Lives and Communities" is now in the bookshelf section of See Change Magazine Website.


text:
<!DOCTYPE html>

  <meta charset="utf-8" />
  <meta http-equiv="X-UA-Compatible" content="IE=edge" />
  <meta name="HandheldFriendly" content="true" />
  <link rel="shortcut icon" href="https://www.epa.gov/sites/all/themes/epa/favicon.ico" type="image/vnd.microsoft.icon" />
  <meta name="MobileOptimized" content="width" />
  <meta http-equiv="cleartype" content="on" />
  <meta http-equiv="ImageToolbar" content="false" />
  <meta name="viewport" content="width=device-width" />
  <meta name="version" content="20161218" />

  <meta name="DC.description" content="" />
  <meta name="DC.title" content="" />
  <title>
  Wyoming EPA/EPSCoR Proposal - Strategic Improvement Plan|

  Research Project Database | Grantee Research Project | ORD | US EPA</title>

  <meta name="keywords" content="" />
  <link rel="shortlink" href="" />
  <link rel="canonical" href="" />
  <meta name="DC.creator" content="" />
  <meta name="DC.language" content="en" />
  <meta name="DC.Subject.epachannel" content="" />
  <meta name="DC.type" content="" />
  <meta name="DC.date.created" content="" />
  <meta name="DC.date.modified" content="2003-02-13" />

  <link type="text/css" rel="stylesheet" href="https://www.epa.gov/misc/ui/jquery.ui.autocomplete.css" media="all" />
  <link type="text/css" rel="stylesheet" href="https://www.epa.gov/sites/all/themes/epa/css/lib/jquery.ui.theme.css" media="all" />
  <link type="text/css" rel="stylesheet" href="https://www.epa.gov/sites/all/libraries/template2/s.css" media="all" />

	<link rel="alternate" type="application/atom+xml" title="EPA.gov All Press Releases" href="https://www.epa.gov/newsreleases/search/rss" />
	<link rel="alternate" type="application/atom+xml" title="EPA.gov Headquarters Press Releases" href="https://www.epa.gov/newsreleases/search/rss/field_press_office/headquarters" />
	<link rel="alternate" type="application/atom+xml" title="Greenversations, EPA's Blog" href="https://blog.epa.gov/blog/feed/" />

Jump to main content

  <hgroup class="site-name-and-slogan">

US EPA

United States Environmental Protection Agency

  </hgroup>
  <form class="epa-search" method="get" action="https://search.epa.gov/epasearch/epasearch">
    Search
    <input class="form-text" placeholder="Search EPA.gov" name="querytext" id="search-box" value=""/>
    <button class="epa-search-button" id="search-button" type="submit" title="Search">Search</button>
    <input type="hidden" name="fld" value="" />
    <input type="hidden" name="areaname" value="" />
    <input type="hidden" name="areacontacts" value="" />
    <input type="hidden" name="areasearchurl" value="" />
    <input type="hidden" name="typeofsearch" value="epa" />
    <input type="hidden" name="result_template" value="2col.ftl" />
    <input type="hidden" name="filter" value="sample4filt.hts" />
  </form>

Contact Us

Project Research Results

Final Report

2004 Progress Report

2003 Progress Report

                      19 publications for this project

                        4 journal articles for this project

Related Information

Research Grants

P3: Student Design Competition

Research Fellowships

Small Business Innovation Research (SBIR)

Grantee Research Project Results Search

      Wyoming EPA/EPSCoR Proposal - Strategic Improvement Plan

    EPA Grant Number: R829426E01

    Title: Wyoming EPA/EPSCoR Proposal - Strategic Improvement Plan

    Investigators:
     Bergman, Harold L.

        Current Investigators:

             Hall, Robert O.
            ,
             Ben-David, Merav

      Institution:

      University of Wyoming

    	EPA Project Officer:

           Winner, Darrell

      Project Period:
      July 17, 2002 through
        September 30, 2004
          (Extended to July 14, 2005)

        Project Amount:

          $39,269

      RFA:
      EPSCoR (Experimental Program to Stimulate Competitive Research) (2001)

        		RFA Text |
          Recipients Lists

      Research Category:

          EPSCoR (The Experimental Program to Stimulate Competitive Research)

Description:

The objective of this project is to enhance the competitiveness of environmental research in Wyoming through aiding young researchers and enhancing recruitment of students to environmentally-related careers.

Approach:

The Wyoming EPA/EPSCoR Project will serve to facilitate/accelerate
  the progress of at least two young researchers toward achievement of nationally
  competitive status. Further, the research will provide opportunities for enhancing
  environmentally-related human resources through the involvement of high school,
  undergraduate and graduate students. Synergistically with the newly created
  Institute for Environment and Natural Resources, the conduct of the SEER project
  entitled "Influence of bio-pollution on ecosystem processes: the impact
  introduced lake trout on streams and terrestrial predators in Yellowstone National
  Park" will play an important role in the sharpening of communication with
  State and Federal agencies concerned with the environmental sciences and natural
  resource management. The SEER project is consistent with recently articulated
  research and infrastructure goals of the University of Wyoming and the overall
  strategic goals of the state's EPSCoR program. Site visits by experts from some
  of the country's top research universities, and invited campus presentations
  by nationally recognized authorities will reduce the sometimes limiting isolation
  experienced by University researchers.

Expected Results:

The project will support the conduct of research important
  to the management of expansive environmental resources and the development of
  new technologies both important to the state's economy and, concomitantly, act
  to amplify the State's research infrastructure.

Publications and Presentations:

        Publications have been submitted on this project: View all 19 publications for this project

Journal Articles:

          Journal Articles have been submitted on this project: View all 4 journal articles for this project

Supplemental Keywords:

      RFA, Scientific Discipline, Geographic Area, Water, ECOSYSTEMS, Ecosystem Protection/Environmental Exposure & Risk, estuarine research, Ecology, Aquatic Ecosystems & Estuarine Research, State, Aquatic Ecosystem, Biochemistry, Ecological Monitoring, Ecology and Ecosystems, bioassessment, estuaries, biopollution, marine biology, Yellowstone Park, lakes, algal blooms, strategic improvement plan, aquatic ecosystems, environmental indicators, water quality, Wyoming

Progress and Final Reports:

                2003 Progress Report

                2004 Progress Report

                Final Report

Top of Page

 The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA.  Conclusions drawn by the principal investigators have not been reviewed by the Agency.

Main menu

Environmental Topics

Laws & Regulations

About EPA

Discover.

Accessibility

EPA Administrator

Budget & Performance

Contracting

Grants

No FEAR Act Data

Privacy and Security

Connect.

Data.gov

Inspector General

Jobs

Newsroom

Open Government

Regulations.gov

Subscribe

USA.gov

White House

Ask.

Contact Us

Hotlines

FOIA Requests

Frequent Questions

Follow.

Facebook

Twitter

YouTube

Flickr

Instagram

Last updated on Thursday, February 13, 2003

redpajama_set_name: RedPajamaGithub


No one knew where the money had come from except for Hazel, her attorney, and the bank teller who opened the checking account and deposited the check into it.
Hazel signed the paper for the new Debit account activation and handed it to the teller, who was tall and had short wavy hair and was wearing a bright blue sweater. Hazel liked the spot of color among the other professional grays, whites, and browns of the other tellers' clothes.
"I'll be going out of the country soon, with this account. Do I need to do any paperwork for that?" She asked the teller.
In the space where "countries traveling to" was the heading, she wrote in bold capital letters "WORLD TOUR--anything is possible". Beneath that, just to be safe, she listed the first 5 countries that came to mind.
She thought about adding "Antarctica," but she didn't want to raise suspicion. The Teller raised her eyebrows and a delighted smile crossed her face.
"Sounds like quite a trip!"
"Yes, it does." said Hazel.
Her friend Jamie agreed to keep the cat for a year. After all, Ampersand was quite a young and appealing cat, just out of kittenhood. A prowling, playful, clean, and independent animal.
Hazel felt the slightest twinge of missing her pet as she handed Jamie the carrier and box of food, toys, and supplies. Jamie helped her pull the scratching post from the trunk and set it in the driveway. Jamie's eyes widened at the sight of a box of library-labeled travel books.
"First?" said Hazel, "I thought I'd try Switzerland. Mountains sound nice. Mountains and snow and cheese and hot chocolate."


You wont have ant grievances with this General Grievous costume. General Grievous is one of the supporting villains in the Star Wars franchise and in the very successful movie Star Wars Episode III: Revenge of the Sith. This costume features a realistic General Grievous mask, General Grievous one piece jumpsuit with attached red cape. This costume also features a chest piece, shoulder pieces, gauntlets and shin guards.


text:
New York State Office of Information Technology Services Among Winners of 2018 Best of New York Awards
ITS Honored with Best of New York Awards by Center for Digital Government, Recognizing Contributions to Advancing IT Innovation in New York State
The New York State Office of Information Technology Services (ITS) today received several 2018 Best of New York Awards in the categories of Best Application Serving the Public, Best Application Serving an Agency's Business Needs, Best IT Collaboration Among Organizations, and Best Business Analysis Project.
In its 15th year, the Best of New York Awards program recognizes public-sector professionals and local government organizations for their dedication and contributions to advance information technology in New York State.
"Congratulations to the 2018 Best of New York awardees!" said Robert H. Samson, New York State Chief Information Officer. "ITS is fortunate to have many talented teams working hand in hand with our agency clients to integrate technology solutions to improve New York State government. The awards reflect how ITS has worked to deliver innovation that matters for all New Yorkers. Kudos on a job well done."
"We are honored to present this year's Best of New York winners and recognize their exceptional dedication to enhancing services for New Yorkers. New York's government has achieved considerable innovation this year, and we are confident the projects recognized at this summit will provide services to improve the lives of citizens and businesses statewide," said Teri Takai, Executive Director of the Center for Digital Government.
Winners are selected based on specific criteria, including collaboration among agencies, innovative use of technology, economic benefits, and improving public services and business processes.
ITS projects receiving 2018 Best of New York awards include:
Best Application Serving the Public for the development of the New York State Warrant Notification Application. The app, developed in partnership with the NYS Division of Criminal Justice Services (DCJS) and the New York State Department of Corrections and Community Supervision, automates and enhances public safety through the automated, real-time delivery of warrant notifications to police, probation and parole officers, and correctional facilities.
Best Application Serving an Agency's Business Needs for the implementation of Acumatica, a cash and inventory tracking system developed in partnership with the Office for People With Developmental Disabilities (OPWDD). Acumatica allows OPWDD to efficiently and cost-effectively manage and protect the specialized assets of individuals residing in state-operated residential programs (group homes).
Best Application Serving an Agency's Business Needs for the Food Safety Laboratory Information Management System Mobile Application developed for the NYS Department of Agriculture and Markets. This app improves food safety processes and furthers the agency's mission to protect public health by modernizing the way food safety inspectors collect, submit, and review food sample data.
Best IT Collaboration Among Organizations for the ITS Enterprise Content Consolidation project. ITS led a massive digital content transformation involving multiple agency clients. The project improved the security, stability, and resiliency of the State's critical applications. It moved legacy content management applications and its business data into the new Enterprise Content Management platform hosted at the Excelsior Cloud, New York State's state-of-the-art data center.
Best Business Analysis Project for the Open FOIL NY Online Webform and Workflow Application. The Open FOIL NY webform provides a centralized online location and uniform method to file Freedom of Information Law requests with 59 State agencies and public authorities, and the agency FOIL workflow application is uniquely configured for each agency to streamline their FOIL request processing. The Open FOIL NY program has already expanded to include the Open FOIL NY website, where New York is the first state in the nation to provide an open-access records request webform that allows the requester to select multiple state agencies for a single records request.
The Best of New York Awards were presented during the annual New York State Digital Government Summit. The Summit, hosted by the Center for Digital Government and Government Technology, is one of the largest technology conferences for state and local government held in New York. This year's Summit provided attendees opportunities for professional development and networking, the ability to exchange knowledge and ideas with diverse colleagues, and to learn about cutting-edge technology.
Theresa L. Egan, Executive Deputy Commissioner of the New York State Department of Motor Vehicles, was honored as the eighth recipient of the 2018 Hugh L. Carey Leadership Award for Outstanding Public Stewardship during a special awards ceremony at the Summit. The award was created in the memory of the late Governor Carey to recognize and honor a New Yorker who, through his or her commitment to public service, has demonstrated leadership, dedication and guidance to improve the future well-being of all New Yorkers by opening doors to innovations.
Executive Deputy Commissioner Egan was selected for her leadership in making the agency more effective and efficient through technology, partnerships, and collaboration.
For more information on the 2018 NYS Digital Government Summit, visit http://www.govtech.com/events/New-York-Digital-Government-Summit.html.


text:
Home » Lift Every Voice and Sing (Hardcover)
Lift Every Voice and Sing (Hardcover)
By James Weldon Johnson, James Weldon Johnson (Text by)
James Weldon Johnson (1871-1938) was a prolific writer and legendary civil rights activist who produced several novels, a pioneering work of cultural history, the first major anthology of black poetry, and numerous treatises on race relations. He served as U.S. consul to Venezuela and Nicaragua and as secretary of the NAACP.
Publisher: Bloomsbury Children's Books
Juvenile Nonfiction / Music / Songbooks
Juvenile Nonfiction / People & Places / United States / African American
Hardcover (February 1993): $15.95
Paperback (January 1995): $6.95
Library Binding (February 1993): $15.85


Powerful video! Thanks for sharing!
Together we all make a difference.
Ugh. Thank you for that reminder of why I am lucky to have lost him. I'll cry. Hug.
It is a poignant reminder.
cry too. Hugs right back.
I agree, we just keep working toward that one day. Thank you.


text:
Level up. Earn rewards.
Your XP: 0
Rank: Nooblet
Sign in to level up now.
GAMERS DECIDE
Covering The Best In Video Games, Esports, Movies and Geek Culture
PC Game Trailers
Fifa 19 Best Strikers That Score Amazing Goals (Top 10)
Updated: 01 Feb 2019 2:43 am
CR7 FIFA 19's Cover Boy
BY: Izuchukwu Morah
Which Fifa 19 strikers can score totally awesome goals?
The work of a striker is to score goals, but at times, you just want some of those goals to be a bit more than just a simple goal. FIFA 19 came with several cool updates including timed-finish; a way of increasing shot accuracy and power. Let's have a look at some of the best strikers in FIFA 19 with the potential to score that amazing goal you've been looking for!
10. Harry Kane (Spurs)
Harry Kane, England's captain and one of the PL's top strikers.
The English-man, Harry Kane plays for Tottenham Hotspurs as their first striker. He was dubbed to be a 'one season wonder' but has continuously proved all his critics wrong, long since winning the BPL's highest goal scorer consecutively and being a runner up once, captaining the English national team to the Semi-finals and winning the Golden Boot at last years FIFA World Cup.
STRIKER STATS:
PACE: 70
DRIBBLING: 81
DEFENCE: 47
PHYSICALITY: 83
PASSING: 79
SHOOTING: 90
WHAT'S GREAT ABOUT HARRY KANE?
Kane is an all round striker; good with both his feet and his head, physical, tall, and still good on set pieces.
As far as one time shots are applied, Kane is at the top when it comes to scoring from a first touch.
STRIKING POWER RATING: 75/100
9. PIERRE-EMERICK AUBAMEYANG (ARSENAL)
Gabon's captain is one of the fastest strikers in the game.
The Arsenal striker became well known in his time at Borussia Dortmund having scored 98 goals before his move to the Emirates.He's also the captain of the Gabonese team. Auba is a smart player and is mostly known for his high acceleration and pace.
WHAT'S GREAT ABOUT AUBAMEYANG?
Aubameyang is one of the fastest players on FIFA 19, if not the fastest. He's effective on counters with long balls, giving you enough time to choose how to score.
You can easily shift Auba to the wing and he'll still be effective with just his pace.
8. Edinson Cavani (PSG)
The Uruguayan striker is the clubs record goal scorer.
Being PSG's record goal scorer isn't something you become from being average. While at Napoli, Cavani showed all his potential, winning the leagues top scorer in his 3rd season there before switching over to the giants of Paris. At 31 years of age, it doesn't look like he's planning to stop scoring anytime soon.
WHAT'S GREAT ABOUT CAVANI?
Cavani is a "warrior" type player that doesn't mind getting dirty or being in a good physical battle for the ball.
Asides being strong, Cavani can play in any attacking role you might put him in and still be able to score from long or short distances with good accuracy.
7. Antoine Griezmann (ATLÉTICO MADRID)
The World Cup winner, was named Man of The Match in the Finals match against Croatia.
At the age of 27, Antoine Griezmann has achieved more than most ever expected of him. The French striker was initially an all out winger, but was converted to a main Striker. He has since been named La Liga player of the year, won a Europa League, been nominated for FIFA's The Best Men's Footballer, the Ballond'Or, UEFA Super Cup, and of course a World Cup where he was awarded a Silver Boot for the 2nd highest goals scored, and a Bronze Ball for the tournament's 3rd best player.
WHAT'S GREAT ABOUT GRIEZMANN?
With such a small stature he's still such a threat when it comes to aerial balls into the box.
Most left- footed players have high shot accuracy. This of course includes Antoine who's also pacey and can comfortably play in several attacking positions.
6. Romelu Lukaku (MANCHESTER UNITED)
The Belgian Striker finished joint 2nd in goals at the 2018 FIFA World Cup. (cc:Torres IMG)
The former Everton striker became the most expensive Belgian player of all time after his transfer to Old Trafford, home of Man United. He is currently Belgium's all time leading goal scorer. He received the Bronze Ball in last years FIFA World Cup for being the joint 2nd highest goal scorer in the tournament, the Silver Ball being given to Antoine Griezmann who went on to win the tournament with France. Belgium went on to finish 3rd in the tournament.
STRIKER STATS
OVERALL:87
WHAT'S GREAT ABOUT LUKAKU?
For someone of such a bulky size, Lukaku can still out pace a lot of defenders.
The Belgian is a "power" striker, one of the most physical players, easily bullying past defenders with strength, pace, and a high shot power.
5. Robert Lewandowski (Bayern Munich)
A goal scoring machine, and record Polish Player of The Year Awardee.
The Polish captain really came into footballing limelight during his time with Borussia Dortmund, especially in the UEFA Champions League. His time at Bayern hasn't been any less impressive, winning the Bundesliga title his first 4 consecutive seasons, finishing as top scorer twice. Asides winning the Polish player of the year a record 7 tines in a row, one of his popular moments came in a match against Wolfsburg where he scored 5 goals in 9 minutes, the fastest in any major European League as far as records started being kept.
WHAT'S GREAT ABOUT LEWANDOWSKI?
Lewandowski is an all-round striker blessed with pace, physicality, positioning, heading, and yet still good with both feet and good at set pieces.
Compared to a lot of top strikers, he's talented at one touch shots.
4. Kylian Mbappe (PSG)
Kylian Mbappe has been said to be one of the next players to potentially take the mantle of World's Best.
There's a very good reason for this 20 years old to be the 2nd most expensive footballer ever. With great flare and enthusiasm, Kylian Mbappe took the world by storm after helping Monaco win their first Ligue 1 title in over 17 years. Paris Saint-Germain immediately picked him up and he immediately made an impact, slotting himself into the first team and scoring constantly. After achieving several personal landmarks at the 2018 FIFA World Cup, which he went on to win with France, he was named the Best Young Player at the tournament, and finished the top joint 2ndhighest goal scorer.
WHAT'S GREAT ABOUT MBAPPE?
The young ace may not primarily be a striker, but he can play as one comfortably depending on your formation.
Mbappe is one of the fastest players on FIFA 19, with a pace even greater than Aubameyang's.
Speed asides, Mbappe is one of the most direct players you can find, thus the low defensive stats. Also, he has a 5- star skills rating.
3. Luis Suarez (BARCELONA)
Luis Suarez has won the top scorer in every league he has played in as a pro.
Less appreciative sports spectators will mainly remember Luis Suarez for his biting incident on Italian defender Chiellini at the 2014 FIFA World Cup, but this doesn't stop the fact that he is without doubt, one of the most proficient strikers in football history. He has won 2 European Golden Shoe awards, an Eredivisie Golden Boot, a Premier League Golden Boot, broke Ronaldo and Messi's 6 year dominance by winning the Pichichi for La Liga's top scorer in 2016, and is Uruguay's all time leading goal scorer.
WHAT'S GREAT ABOUT SUAREZ?
El Pistolero, as some call him, is FIFA 19's highest rated all out striker with a rating of 91.
His greatest threat comes from his positioning and attacking prowess. Not the fastest of strikers, but he'll easily take on any defender in a 50-50 battle for the ball.
2. Lionel Messi (BARCELONA)
Time after time, Leo Messi has proved he's amongst the best to have ever been on a pitch.
Considered by many as the Best Player in the world, possibly of all time, Leo Messi has constantly dished out year after year of unbelievable performances. The footballing world has gotten tired of listing out individual and team records he breaks or surpasses every other match. Perhaps, the only achievement he hasn't accomplished is a trophy as a senior player for Argentina, though coming close on several occasions.
WHAT'S GREAT ABOUT MESSI?
Messi is one of the most versatile players on FIFA 19. Known for his wing play, he can make a very good striker or even as an attacking or central midfielder depending on your formation.
Leo Messi along side Cr7 is the highest rated player on FIFA 19, being one of the best dribblers and shooters both in-game and in reality.
1. Cristiano Ronaldo (JUVENTUS)
Cristiano inspires hard work and constant determination into his vast fanbase.
Along side Leo Messi, Cristiano Ronaldo (cr7) is seen as one of the best players in the world. Bringing both flare and positivity to the footballing world, he proved how good he was at England for Manchester United, did likewise with Real Madrid in the La Liga winning 3 consecutive UCL titles, and is currently amongst the top scorers in just his first season for Juventus.
WHAT'S GREAT ABOUT CR7?
As far as games are concerned, Ronaldo has been one of those players that can score from odd distances and impossible angles, with high shot power.
You can play Cr7 in any attacking position and he'd still perform brilliantly.
He's an all round player, good with his head, good with both feet, has high acceleration, and high shot power and accuracy.
Being a top striker has so much attached to it. Getting special and spectacular goals is one of those things. There are so many good strikers out there, but if you're looking for that extra something, those listed above are what you need. A few honorable mentions include: Marcus Rashford, Sergio Aguero, Gonzalo Higuain, and Dries Mertens.
10 Best PC Football Games
Best Kits on FIFA 19
Best Formations on FIFA 19
Best Players For Your Career Mode on FIFA 19
More on this topic:
Izuchukwu Morah
Destined to be a wizard, I wave my magical pen with the purpose of bringing the light of knowledge to all humans. Born in the Land of Nigeria but raised in the Kingdom of Maryland, gaming is my motto.
Gamer Since: 2010
Favorite Genre: Sports
Currently Playing: God Of War V/ FIFA 19
Top 3 Favorite Games:Devil May Cry DMC, Call of Duty: Advanced Warfare, FIFA 16
Aguero, a hero to City fans.
Top 15 Fifa 19 Best Kits That Look Awesome
What Are The Best Kits in Fifa 19? You might wonder why football kits are important enough to talk about, but would you like becoming a champion with your team wearing drab and boring looking kits? If you're planning on taking on your FIFA 19 Ultimate Team Weekend League, why not go into it...
[Top 10] FIFA 19 Best Formations
What Are The Best Formations To Use on FIFA 19? September 28th, 2018 was a highly anticipated day for a lot of gamers around the world, with the release of EA Sport's FIFA 19 finally coming through. With it came new leagues, new teams and looks, but also whole new tactical systems and a...
The Best Free To Play Games
Free-to-Play, Sci-Fi, MMO
Players take the captain's chair as they command their own starship and crew.
Adventure, MMORPG, Free-to-Play
An action MMORPG based on the acclaimed D&D fantasy game, epic stories and classic roleplaying await!
Top 20 GD Veterans
1 GalenSt
Reputation: +6
2 Brantml
3 Ridgewip
4 Brianengab
5 Aldendic
6 Woumeft
7 MaxwellDenton
8 TrueInfinity
9 M.Nikolic
Reputation: +10
10 mike25490
11 DavinCing
12 KevenTag
13 MrM0rg0th
14 James Lightning
15 Isaia
16 Ramonzon
17 DerikPag
18 MrsDeadpool
19 kelocok
20 AntLong35
Day * Day12345678910111213141516171819202122232425262728293031
Month * MonthJanuaryFebruaryMarchAprilMayJuneJulyAugustSeptemberOctoberNovemberDecember
Year * Year1970197119721973197419751976197719781979198019811982198319841985198619871988198919901991199219931994199519961997199819992000200120022003
Registration popup thank you page
Humans enter. Bots stay out.
By clicking Sign Up, you agree to our Terms and that you have read our Privacy Policy.
Copyright© 2017 GamersDecide Inc. All rights reserved


Our 25,000 s.q.m workshop that is located in the Huizhou City, Guangdong, enables us to combine the creative, technical and operational aspects of any product with your brand name. We always care about your business. The efficient logistics system of WEO ensures that millions of VM products are handled professionally and delivered to the right stores. Our globally recognized brands include Chanel, CK, H&M, Ocean Park and HK International Theme Park.


When you run a small business in Edmonton, or anywhere else for that matter, it becomes crucial to maintain accounts properly, so that you don't get into legal hassle of any sort. And while it might seem like a good idea to maintain the accounts yourself and save money, the decision might backfire if you are not knowledgeable about the laws and regulations related to business accounting and taxation.
Maintaining detailed records of purchases and sales along with details about receipts can help you avoid legal hassles at the time of auditing. Plus, it can also give you a clear picture of your business, helping you track profits/losses on a monthly basis and identifying business areas where you need to be more efficient to run your business successfully.
This is essential to run your business legally. Failing to file your tax returns on time can lead to heavy penalties, or even visits from the income tax officials. You don't need that kind of heat over the simple task of filing a few documents.
Governments often offer tax incentives to small businesses, helping entrepreneurs run them without too much of a financial burden. A tax adviser can help you take advantage of these by showing you how to maintain the right paperwork and distribute your investment wisely.
Running a small business makes it essential to be careful with your funds, so that you don't run out of capital in the middle of a busy season. Get tax advice from reliable accountants and tax advisers in Edmonton to run your business profitably for a very long time to come.
Security Code* 1 + 3 = ??


God Believes in Love Edition by Gene Robinson and Publisher Vintage. Save up to 80% by choosing the eTextbook option for ISBN: 9780307961754, 0307961753. The print version of this textbook is ISBN: 9780307957887, 0307957888.