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The Turing Trust
Supporting education in Africa through sustainable micro-development. The Turing Trust is an African micro-development charity set up in 2009 to develop sustainable rural schools in Ghana. We fundraise through our enthusiastic sup View moreSupporting education in Africa through sustainable micro-development. The Turing Trust is an African micro-development charity set up in 2009 to develop sustainable rural schools in Ghana. We fundraise through our enthusiastic supporters in our local communities to help the schools and wonderful communities who have made such a strong impression on the founding members of the Turing Trust. With all of this support we are able to make huge changes to the lives of the children we work with in Ghana. Since the Trust began we have enabled 20 extra students to gain an education each year by constructing a girls dormitory, we have built and furnished a computer lab enabling a whole community to access to the digital world, donated over £40,000 and 85 computers to our associated schools in Ghana and most importantly ensured that hundreds of students have been able to gain an education. We believe that charity should be as transparent as possible whilst providing the maximum benefit for the minimum cost. For these reasons we regularly publish our most detailed accounts online and use the power of volunteering to keep our admin costs below 1% of our annual income. To see the results of our policies of full disclosure please go to our Finances web-page for more details. We hope that by providing such up front disclosure we might encourage other worthy charities to follow suit and join us in providing full disclosure to the philanthropic world. For more information about the Turing Trust please visit www.turingtrust.co.ukSign up for free & support this cause
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British English: /rɪˈkwʌɪə/ American English: /rəˈkwaɪ(ə)r/
Translation of require in Italian:
transitive verb
- 1 (need)(person, client, company)this machine requires servicing
avere bisogno di (help, money, staff, surgery)questa macchina ha bisogno di riparazionitake the tablets as required "does Madam require tea?" [formal]"la signora desidera del tè?"
- 2 (demand)(person, law, job, situation)to be required by law to require that …
esigere, richiedere (explanation, funds, obedience, qualifications)ordinare che …to require something of o fromesigere qualcosa dato be required to doessere tenuto a farethis job requires an expertquesto lavoro richiede l'intervento di un esperto
Definition of require in:
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subset: commoncrawl


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The adidas Originals Craft Pack is made up of possibly 4 of the most iconic sneakers in the culture's history. The Stan Smith, Samba, Superstar and Forum Mid showcase the esteemed history adidas have had. The Craft Pack brings a handmade and luxurious feel to the sneakers, take a look at the full collection below.
Link: Tenisufki


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Dolomites (Italy) - Tofana Rozes (3225 m)
Thanks for using my stock!
That is very pretty
Nice viewpoint!
I love how you can see the trees getting progressively smaller as the rock tiers climb further up the mountainside.
Is a beautiful and terrible mountain, during the First World War was the scene of fierce fighting between Italian and Austrian and still bears the signs: trenches and tunnels.
Ci sono stata ad Agosto LOL
Io ero solo di passaggio sulla statale, mi sono giusto fermato a scattare la foto. Sarebbe stato un peccato mortale non farla.
oh! ♥


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iHerb 顾客评论
Many Health Benefits
6 个顾客认为以下的评论有帮助
greenspots发表于 May 11, 2012
I've taken two or three teaspoons of this organic cayenne powder a day, in about three or four ounces of warm water, for about a year and a half. I have Raynaud's disease and before I started taking the cayenne, my hands and feet were ALWAYS cold, even in the summer. A short time (I don't remember exactly how long it was) after starting taking the cayenne, I was shocked to realize my hands and feet were no longer cold. I don't even have to wear socks to bed in the winter, like I used to. Cayenne is great for circulation, as well as many other things. I feel Starwest Botanicals is a very good brand and highly recommend it.
Good & Hot!
2 个顾客认为以下的评论有帮助
MikeMember发表于 Jan 24, 2013
This cayenne has a nice flavor and is hot enough to satisfy.
2 个顾客认为以下的评论有帮助
Reviewer2308938发表于 Oct 26, 2010
Great quality
Just the trick!
4 个顾客认为以下的评论有帮助
Reviewer2480298发表于 Jan 04, 2011
Definitely a great benefit to anyone experiencing inflammation. I love it taken by the tablespoon in a homemade tomato soup with cornbread...goes down better for me than in hot drinks, and I feel the effects within 30 min. from the pain disappearing in my hip to the strong heat in my feet...circulation is never a problem when I remember to take my cayenne!
Good Product
1 个顾客认为以下的评论有帮助
CindyW发表于 Jun 25, 2013
Great smell, taste, and texture. I fill empty capsules with cayenne and take it internally as a supplement. It kills cancer cells!


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RED SOX OWNER WANTS TO DESTROY FRANK'S MCMANSION: The BOSTON HERALD reports that Red Sox owner John Henry recently purchased a $16M Boston-area estate belonging to Dodgers owner Frank McCourt.
The estate includes a 13,000-square-foot red brick Georgian Revival mansion and a 5,000-square-foot guest house on an adjacent lot.
Henry's plans for the property? Level it - at a cost of another $16M!
Herald: "McCourt and his wife, Jamie, spent heavily to renovate the home, but Henry has come to the conclusion that it is easier to start from scratch than to try to remake what is essentially a 1930s home, sources familiar with the planning say."
Acquiring a demolition permit from the local Brookline (MA) community won't be easy, as the historical society will surely want to preserve the 75-year-old main house. The Herald also reports that the house might be saved "if someone famous … lived in the house."
The McCourts are the only residents we know about, so someone may as well cue the wrecking ball. On the bright side, if anyone has experience with tear-downs, it's the McCourts.


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Deviant Art
The Magical Scarf of Ink-ThrowingA young woman named Lucy loved making art, and practiced ink-throwing all day long to become the very best in all her town. But one day, she was completely stumped. She looked around her room, full of art pieces featuring mystical tweezers, sci-fi landscapes of a futuristic Ljubljana, and a portrait of Julia Gillard that looked so real, you could start a conversation with it. But nothing inspired her. Had she really created everything there was to create? Depressed, she looked out her window, and made a wish on a nearby scarf for inspiration to return to her. The next morning, she sprung out of bed, and used her skill in ink-throwing to create the most beautiful deviation depicting bouncing parking tickets anyone had ever seen. That night, she shouted out the window, "Thanks, scarf!"The Magical Scarf of Ink-Throwing4 years ago in Create a Story Contest More Like This
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Copyright © 2016 Interactive One, LLC . All Rights Reserved - iOne Millennial.
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I'm counting down my top 10 favorite Christmas songs! Here's #9!
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In other words, it's the perverted imbecile offering candy to unsuspecting victms and enticing them into a beat up van.
God, can it get this crooked?
i love the deliciously contrived example. as tho anyone but hedgies trades sirius to begin with, its barely even a real stock anymore its a traders toy like BAC... "For example, if a doctor trading stocks from his home office wanted to sell 10 shares of Sirius, and donate the proceeds to an orphanage, and didnt care that commissions on the trade equal about half of the proceeds,"
I rather expected a useful and well-explained description of the "Retail LIquidity" program. Silly me. What I've realized, is if firms like Knight are the specialist market makers - then I should treat the US equity market with the same focused aversion that I would a rigged game of roulette in a crooked casino. Markets don't have to be bent, and even Meyer Lansky knew that you had to run an honest casino in order to attract and hold the players. What I wonder is why does it have to get worse and more bent every year? Why not just ban the direct connection of a trading computer to a market trading feed? Just make the trades go thru human fingers - same protocol we used in the old days, to ensure the computers didn't launch the nuclear missles by error, back in the 1960's. The trading "algos" are doing to honest market participants what the CIA Drones are doing to desert Bedouins in Yemen - "death from above" - so quick and effective, you don't even have time to know what got you. Interesting times we live in. Maybe it's just time to rethink the current model.
- Rus
mean while the stock's value is calculated to the 10th power...1.1111111111 so the value paid is more then it's sold for. undermineing the entire stock market...how foul...where does the rest of the money go?


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Garden of therapeutic delights: new targets in rheumatic diseases
- Jean M Waldburger1 and
Affiliated with
- Gary S Firestein1Email author
Affiliated with
DOI: 10.1186/ar2556
© BioMed Central Ltd 2009
Published: 30 January 2009
Skip to main content
DOI: 10.1186/ar2556
© BioMed Central Ltd 2009
Published: 30 January 2009
Advances in our understanding of the cellular and molecular mechanisms in rheumatic disease fostered the advent of the targeted therapeutics era. Intense research activity continues to increase the number of potential targets at an accelerated pace. In this review, examples of promising targets and agents that are at various stages of clinical development are described. Cytokine inhibition remains at the forefront with the success of tumor necrosis factor blockers, and biologics that block interleukin-6 (IL-6), IL-17, IL-12, and IL-23 and other cytokines are on the horizon. After the success of rituximab and abatacept, other cell-targeted approaches that inhibit or deplete lymphocytes have moved forward, such as blocking BAFF/BLyS (B-cell activation factor of the tumor necrosis factor family/B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) or suppressing T-cell activation with costimulation molecule blockers. Small-molecule inhibitors might eventually challenge the dominance of biologics in the future. In addition to plasma membrane G protein-coupled chemokine receptors, small molecules can be designed to block intracellular enzymes that control signaling pathways. Inhibitors of tyrosine kinases expressed in lymphocytes, such as spleen tyrosine kinase and Janus kinase, are being tested in autoimmune diseases. Inactivation of the more broadly expressed mitogen-activated protein kinases could suppress inflammation driven by macrophages and mesenchymal cells. Targeting tyrosine kinases downstream of growth factor receptors might also reduce fibrosis in conditions like systemic sclerosis. The abundance of potential targets suggests that new and creative ways of evaluating safety and efficacy are needed.
The development of new therapies for rheumatic diseases was mainly empiric until recently. Most of the drugs that we used until the 1990s, including standards like methotrexate, were originally discovered for other purposes or were accidentally noted to be beneficial in autoimmunity. As the molecular mechanisms of disease have been unraveled, newer targeted therapies have been a stunning success. Understanding the importance of cytokine networks in rheumatoid arthritis (RA) led to the biologics era with agents that block tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6. These biologics are also effective in other diseases, including seronegative spondyloarthropathies, autoinflammatory syndromes, and perhaps gout.
The most dramatic therapeutic advances in the 'modern' era of rheumatology have focused on anti-cytokine therapy. As the cytokine network becomes increasingly complex, new and exciting possibilities arise. In this section, a few key cytokine targets are discussed.
Of the cytokines relevant to autoimmunity, IL-17 and its family have perhaps generated the most anticipation. In murine models of autoimmune disease, the Th17 subtype of T lymphocytes that produce IL-17 plays a pivotal role in pathogenesis [1]. While the function of this factor in humans is less certain, it represents a unique T cell-derived factor that could participate in many rheumatic diseases. The IL-17 family comprises six members designated IL-17A through F, with perhaps the most important being IL-17A (which is the cytokine usually called 'IL-17'). IL-17A is found in the synovial fluids of some RA patients and can be detected in T cell-rich areas of RA synovial tissue [2, 3]. It, along with its closest homolog IL-17F, enhances the production of proinflammatory cytokines by fibroblast-like synoviocytes (FLS) and might amplify the effects of macrophage-derived cytokines such as TNF [4]. Blockade of IL-17 with an antibody-based approach is very effective in collagen-induced arthritis (CIA) as well as many other models of inflammation [5].
There are several ways to block IL-17 family members. Conventional methods, such as monoclonal anti-IL-17A antibodies, are currently being developed for RA and psoriasis as well as other autoimmune indications. Subunits of the IL-17 receptor complexes (IL-17RA and IL-17RC) could be used to design soluble antagonists that can bind multiple members, such as IL-17A and IL-17F. The results of IL-17-directed approaches are eagerly anticipated for a variety of indications, including RA and psoriasis.
IL-12 and IL-23 are related cytokines that are secreted by macrophages and dendritic cells after cytokine or Toll-like receptor ligand stimulation. IL-12 is a key inducer of Th1 CD4+ T cells that produce interferon-gamma (IFN-γ), whereas IL-23 contributes to Th17 polarization. Thus, an IL-23-targeted therapy could potentially have a downstream effect on IL-17 production. When T cells are exposed to IL-23, the cells can be directed toward the Th17 phenotype. This is especially true in mice, in which exposure to IL-6 and transforming growth factor-beta (TGF-β) also contributes to Th17 cell production through the activation of STAT3 (signal transducer and activator of transcription 3) and induction of the transcription factor retinoic acid-related orphan receptor (RORγt). The system in humans is not as well defined and TGF-β might not contribute. Nevertheless, an IL-23-targeted therapy could potentially have a downstream effect by limiting the activation of Th17 cells and decreasing expression of IL-17 family genes. The interplay between IL-12 and IL-23 and autoimmunity can be complex; mice deficient in the IL-12 p35 subunit have increased severity of CIA [6]. In contrast, mice lacking the p19 subunit of IL-23 are protected from CIA, as are p40 knockout mice, the subunit common to IL-12 and IL-23.
Even though IFN-γ is the signature cytokine of Th1 cells and is pathogenic in some models of autoimmunity, including proteoglycan-induced arthritis, the IL-12/IFN-γ axis can also be protective in CIA and experimental allergic encephalomyelitis (EAE) [7]. IFN-γ also blocks Th17 development and can potentially enhance regulatory T (Treg) cell response [8, 9]. Strategies that interfere with IL-17 production like IL-12/IL-23 inhibitors or IFNγ can potentially enhance the suppressive activity of Tcells and limit autoimmunity. Treg cell numbers can also increase with other cytokine modulators, such as infliximab [10]. The apparent reciprocal relationship of Treg cells and Th17 cells provides a potential way to alter immune responses and restore homeostasis through cytokine modulation.
IFN-γ is expressed at relatively low levels in the rheumatoid synovium and exerts anti-inflammatory effects in vitro and in some arthritis models [11]. IFN-γ administration in RA shows minimal efficacy and caused disease exacerbation in multiple sclerosis. Patients could only tolerate a dose considerably lower than required to suppress arthritis in mouse models. Based on the results of clinical and preclinical studies, a selective IL-12-directed agent that interferes with Th1 cell differentiation without a major effect on Th17 cells might be less attractive.
Mouse and human T-cell systems clearly differ in many respects, which makes extrapolation from murine models difficult [12]. As noted above, TGF-β is critical for Th17 differentiation in the mouse but might be less important in human cells. A large percentage of human IL-17-positive T cells also produce IFN-γ. While blocking Th17 cells might be sufficient in mice, efficacy could require suppressing both the Th1 and Th17 pathways in humans. This approach could involve interfering with IL-23, which is required by Th17 cells for effector function. IL-23 p19 levels were higher in RA than osteoarthritis synovial fluids in one study [13]. However, another group detected low levels of heterodimeric bioactive IL-23 in only a fraction of RA synovium samples [14].
A monoclonal antibody against p40, the subunit common to IL-12 and IL-23, showed remarkable efficacy and a favorable safety profile in inflammatory bowel disease and psoriasis [15–17]. The results of a placebo-controlled phase II study in psoriatic arthritis are also available. Patients were treated every week for 4 weeks and received two other injections at weeks 12 and 16. ACR20 (American College of Rheumatology 20% improvement criteria) responses at 12 weeks were achieved in 42% of patients compared with 14% in the placebo group. ACR50 and 70 responses were also statistically significant (25% versus 7% and 10% versus 0%, respectively) [18].
The small molecule STA-5326 is being evaluated in a phase II trial in RA. In vitro, this compound blocks IL-12, IL-23, and IFN-γ production by cultured peripheral blood mononuclear cells, although the mechanism is not well established. In an open-label study, STA-5326 decreased clinical activity scores in Crohn disease patients. The clinical trials might help investigators to understand the role of the IL-12/IL-23 axis in different forms of human autoimmune disease.
Elevated levels of IL-15 are expressed in the synovium of RA patients and have been implicated as a mediator of TNF production by macrophages [19]. This cytokine can also participate in joint inflammation by attracting neutrophils and T lymphocytes and by triggering the proliferation of memory CD8+ T cells. IL-15 can be bound to the plasma membrane or secreted, while a shorter isoform remains intracellular. The IL-15 receptor complex is trimeric and comprises the γ subunit (shared with IL-2, IL-4, IL-7, IL-9, and IL-21) and IL-2/15 β chains (shared with IL-2). The IL-15R α chain confers specificity toward IL-15. A human monoclonal antibody that binds IL-15 showed a modest ACR20 response in a phase II clinical trial at the highest dose, supporting a possible contribution of IL-15 in RA. These preliminary results are encouraging, although a second study failed to show significant benefit.
Elevated levels of BAFF/BLyS (B-cell activation factor of the TNF family/B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) are found in the serum of patients with RA, SLE, and Sjögren syndrome. These two cytokines are members of the TNF superfamily and are expressed by various cell types, including monocytes, dendritic cells, osteoclasts, and synoviocytes [20]. Both bind to receptors expressed on B cells, known as BCMA (B-cell maturation protein) and TACI (transmembrane activator and CAML interactor). BAFF receptor 3 (BR3) recognizes only BAFF/BLyS. These molecules perform similar functions in B-cell development and survival, Ig class switch, and costimulation.
Several different biologic strategies to block BAFF/BLyS and APRIL are being developed. Belimumab is a fully humanized anti-BAFF antibody that showed minimal efficacy in a phase II trial in RA [21]. Belimumab was also evaluated in a phase II study in patients with active SLE. It failed to meet its primary endpoint, but subgroup analysis suggested that it might improve or stabilize disease activity in some patients [22]. One potential problem with belimumab is that it does not block APRIL and hence might not have sufficient effect on B-cell maturation. TACI-Ig is designed to function as a decoy receptor with both anti-BLyS and anti-APRIL activity. Another agent, the BAFF receptor-Ig fusion protein, inhibits only BAFF. TACI-Ig is being evaluated in RA and SLE, and preliminary studies suggest that there is a significant decrease in serum immunoglobulins. Anti-BR3 antibodies with cell depletion activity and BR3-Fc are being developed for similar indications [21, 23]. The respective merits of strategies involving BLyS and APRIL are difficult to compare because their respective roles in humans are not yet fully understood.
The lymphotoxin (LT) system is also part of the TNF superfamily and includes lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells (LIGHT), LTα, and LTβ [24]. All three ligands can bind the LTβ receptor (LTβR) and can participate in the development of the immune system and lymphoid organization. LTα also binds to the TNF receptors and its function is blocked by etanercept. In addition, LIGHT binds to another receptor, herpes virus entry mediator (HVEM). The LIGHT-HVEM interaction is proinflammatory, but HVEM also binds the B- and T-lymphocyte attenuator (BTLA), which suppresses immune responses.
Decoy receptors designed by linking the LTβR with the Ig Fc domain selectively inhibit the proinflammatory functions of the LT system. This strategy is effective in many animal models of autoimmunity, including CIA, EAE, and murine models of SLE and diabetes [24]. LTβR signaling is required to develop and maintain tertiary lymphoid structures but is dispensable for many aspects of secondary lymphoid organ biology in adults.
In RA, lymphoid structures are seen in the synovium of up to 30% of patients. LTβR-Ig therapy might be especially effective in this subpopulation if these structures play a critical role in local antigen presentation and disease pathogenesis [24]. In addition, synoviocytes can respond to LIGHT, LTα, and LTβ with the release of proinflammatory mediators. Early results from RA patients treated with LTβR-Ig have demonstrated some benefit, although a larger study reportedly did not demonstrate sufficient efficacy to warrant continued development for RA. However, other autoimmune diseases, such as SLE, are additional indications that could be evaluated with this molecule. Careful monitoring of host defense will also be needed given the important role of LTβ in germinal center organization.
Inflammatory and immune cell recruitment to target tissue is a hallmark of autoimmune diseases. This process is regulated by a class of proteins called chemokines as well as many small-molecule chemoattractants [25]. More than 40 chemokines have been identified and many can bind to more than one receptor. In addition, about half of the 20 chemokine receptors, which are 7-transmembrane G-protein coupled receptors (GPCRs), recognize multiple chemokines. Which chemokine or receptor to block in a particular disease remains a difficult question, and targeting individual chemokines has not been fruitful due to redundancy in the system.
On the other hand, blocking GPCR chemokine receptors by synthesizing small-molecule inhibitors that block the interaction of multiple chemokines with an individual receptor has been more encouraging. The chemokine/receptor pairs CXCL13/CXCR5, CCL21/CCR7, and CXCL12/CXCR4 contribute to the formation of ectopic lymphoid structures that are found in most autoimmune diseases and could be targeted for autoimmunity. CCR5, CCR2, and CCR1 are implicated in RA and might be involved in recruitment to inflammatory sites like synovium.
Inhibition of CCR1 and CCR2 was not effective in RA [26]. The results for the CCR1 antagonist were somewhat surprising in light of a synovial biopsy study suggesting that synovial macrophages were depleted. CCR2 is a more complex chemokine, and the effect of CCR2 deficiency or CCR2 inhibitors in animal models varies depending on the model. This approach is especially interesting in humans because CCR2 (along with CCR6) is a key receptor expressed by human Th17 cells [27]. The failure of CCR1 and CCR2 antagonists could be related to pharmacokinetic issues, lack of pathological relevance of these targets, or redundancy in the receptor system.
CCR5 received considerable attention when it was discovered that individuals with a deletion in this gene are protected from HIV viral entry. Epidemiologic studies also suggest that the CCR5 deletion could decrease severity of RA, although this is controversial. A small-molecule inhibitor of CCR5 is now approved for patients with HIV. CCR5 is expressed on T cells and macrophages and binds to the inflammatory chemokines MIP-1α (macrophage inflammatory protein-1-alpha) and RANTES (regulated on activation normal T cell expressed and secreted) that are highly expressed in RA. Blocking CCR5 provides protection from arthritis in the CIA model [28]. Phase II clinical trials with CCR5 inhibitors are in progress for RA.
Many other chemokines have been considered targets for rheumatic diseases. For instance, stromal derived factor-1 is a potential target and is relatively simple to block since, unlike many other chemokines, it has only a single receptor (CXCR4). Chemokines play a role in the organization of lymphoid structures, which are required for antigen presentation and germinal center formation. Disrupting this network by interfering with dendritic cell-derived chemokines, such as CXCL13 or CCL21, could achieve this goal, as could blocking cytokines like LTβ (see above).
A detailed description of the myriad of approaches designed to interfere with immune cell recruitment by blocking either cell adhesion or angiogenesis is beyond the scope of this short review. However, the success of the anti-α4/β1 integrin antibody in multiple sclerosis suggests that it might be useful in other autoimmune diseases that involve recruitment of T cells. Balancing the relative risks of decreased host defense (for example, progressive multifocal leukoencephalopathy [PML]) with potential benefit will be a significant challenge. Approaches that target the β2 integrins, which play a key role in neutrophil recruitment, are very effective in preclinical models but raise significant concerns about crippling host defense. Similarly, angiogenesis inhibitors like anti-vascular endothelial growth factor in cancer and preclinical data suggesting that new blood vessels contribute to inflammation suggest that this approach might be applicable to rheumatic diseases. Selective inhibitors of proliferating endothelial cells, such as AGM-1477 (a derivative of fumagillin), show impressive anti-inflammatory effects in several animal models of inflammatory arthritis.
The efficacy of rituximab, a chimeric anti-CD20 monoclonal antibody, in RA opened up the potential for B cell-directed therapy in rheumatic diseases. The antibody was initially developed to deplete malignant B cells in lymphoma patients by virtue of CD20 expression on mature B cells, but not B-cell precursors or plasma cells. Rituximab causes a prolonged depletion in circulating B lymphocytes in the blood. CD20+ synovial B cells are variably reduced and this is associated with a decrease in synovial immunoglobulin synthesis, especially in ACR50 responders [29]. Clinical response was associated with a decrease in synovial plasma cells in another study [30].
Rituximab contains chimeric mouse-human sequences that might be responsible for some infusion reactions. Human or humanized anti-CD20 antibodies, like ocrelizumab and ofatumumab, are being developed to mitigate this problem [21]. Smaller versions of monoclonal antibodies combine one binding domain, one hinge domain, and one effector domain into a single-chain polypeptide. This new class of drug, known under the acronym SMIP (small modular immuno-pharmaceutical), is also being developed.
Although multiple case reports and open-label studies suggested a benefit of rituximab in SLE patients, the drug did not demonstrate clinical efficacy in the randomized phase II/III EXPLORER trial. The results of another study for lupus nephritis are anticipated. Case reports of fatal PML in severely immunocompromised lupus and cancer patients who received anti-CD20 antibody necessitate careful individual evaluation of the risks and benefits of off-label use.
CD22 is a B cell-specific surface molecule involved in B-cell antigen receptor signaling. A humanized antibody against this regulatory molecule showed modest efficacy in lupus patients in a randomized phase II study [31]. An average reduction of peripheral B cells of 30% can persist up to 12 weeks. Additional regulatory mechanisms, including inhibition of B-cell proliferation, could contribute to the therapeutic activity of this molecule.
CTLA4 is an inducible T-cell surface molecule that inhibits costimulation signaling induced by CD28 engagement with CD80/CD86. Abatacept, a CTLA4-Ig fusion molecule, blocks the interaction between CD80/86 and CD28 and is effective in RA. The success of this approach contrasts with the failure of previous T cell-depleting strategies, such as anti-CD4 antibodies, perhaps because CD4 is also expressed on Treg cells that can suppress inflammatory arthritis.
Other costimulatory molecules are also potential therapeutic targets, although the preclinical data are complex. For instance, blockade of the inducible costimulator (ICOS) is therapeutic in CIA but augments disease in diabetes and some multiple sclerosis models [32]. Subtle differences between human and animal proteins, such as Fc receptors, might contribute to the catastrophic cytokine release syndrome caused in human volunteers by the CD28 superagonist TGN1412 [33]. Nonetheless, the CD80/86-CD28 family remains a promising field for new therapeutic interventions. The interaction between CD40 and CD40 ligand is also attractive, although anti-CD40 ligand antibodies in SLE were complicated by thrombotic disease. Targeting CD40 instead might avoid the activation of platelets, which express CD40 ligand.
FLS are present on the synovial intimal lining. They contribute to the pathogenesis of RA by virtue of their ability to produce cytokines (especially IL-6), metalloproteinases, and small-molecule mediators of inflammation like prostaglandins. Selective targeting of FLS has been difficult until recently, when a relatively unique marker, cadherin-11, was identified as a key protein involved with homoaggregation of synoviocytes in the lining layer of normal synovium [34]. Preclinical models suggest that cadherin-11 blockade disrupts the synovial lining, decreases joint inflammation, and suppresses cartilage damage. This approach is interesting because it could potentially be used in combination with immunomodulatory agents without an adverse effect on host defense.
Inducing or enhancing synovial cell death, especially FLS, is another approach that could be beneficial in inflammatory arthritis. A number of therapies have been considered and demonstrate preclinical efficacy, including using anti-Fas antibodies to induce apoptosis or enhancing expression of intracellular genes like Bim or PUMA (p53 upregulated modulator of apoptosis) [35, 36]. Because the mechanisms of cell death are shared by many cell types, selectively inducing apoptosis in FLS or in the joint can be difficult. Thus, methods to target the synovium selectively might be required.
Intracellular signaling pathways transmit environmental information to the cytoplasm and the nucleus, where they regulate cellular responses and gene transcription. Understanding the hierarchy and pathogenic significance of these pathways in autoimmunity has led to the development of compounds that block several promising targets [37, 38]. Orally bioavailable small-molecule inhibitors are currently the most likely approach, although biologics like small interfering RNA and genes that express dominant negative kinases are also possible. It is likely that the small-molecule approach, though still in its infancy, will advance rapidly over the next decade. If successful, these small compounds could augment or replace more expensive parenteral biologics that are currently the mainstay of treatment. Several hurdles still need to be overcome, including improved compound specificity and the importance of many key pathways for homeostasis and host defense [37].
Drug development efforts in the MAP kinase family have led to the synthesis of several p38 inhibitors. This kinase regulates the production of inflammatory cytokines and chemo-kines in response to TNF or IL-1 in most inflammatory cell types. p38 inhibitors are effective in preclinical models of arthritis and several have advanced into clinical trials [39, 40]. The availability of phase II trial results in RA is limited but they suggest, at best, modest benefit in RA. One major issue that affects the development of some p38 inhibitors is dose-dependent toxicity. Structurally distinct compounds have caused hepatoxicity, which might indicate that this side effect is target-based. In another phase II trial, the p38 inhibitor VX-702 caused Q-T prolongation.
Based on the number of compounds that have been tested, it is clear that targeting p38 will not be as simple as hoped. Several potential alternatives have emerged in recent years, including downstream (MK2) or upstream (MKK3 or MKK6) kinases that are involved in the p38 biology [41, 42]. These strategies could potentially provide some of the benefit of modulating p38 signaling while preserving other essential functions and ameliorate the side-effect profile.
JNK and ERK inhibitors for rheumatic disease are less advanced. JNK controls activator protein-1 (AP-1)-dependent genes, including matrix metalloproteinases (MMPs), and animal studies with JNK inhibitors showed protection from bone damage [43]. However, the available JNK inhibitors have not been developed for rheumatic diseases yet and could have issues related to potency and selectivity. MKK7, an upstream activator of JNK, is the main kinase required for JNK activation after cytokine stimulation of FLS [44]. Since cellular stress events can bypass MKK7 and use MKK4 to stimulate JNK, targeting MKK7 could be safer than broad-acting JNK inhibitors.
Targeting the downstream transcription complex AP-1, such as with decoy oligonucleotides, is another alternative to focusing on JNK. AP-1 consists of dimers that include members of the Jun, Fos, and activating transcription factor protein families that together control a large number of genes, including MMPs and inflammatory cytokines. c-Fos-deficient mice lack osteoclasts and are protected from bone erosions but not inflammation in the TNF transgenic model [45]. A small molecule with anti-AP-1 activity was effective in CIA [46]. Interestingly, this compound also decreased IL-1 levels and joint inflammation, an indication that it had a pronounced effect on AP-1-driven transcription. No significant toxicity was reported during animal testing but this will require careful evaluation in human studies.
ERK plays a major role in the regulation of cell growth and could be an important therapeutic advance in cancer. ERK inhibitors are also effective in some preclinical models of arthritis [47]. The small-molecule inhibitor MEK1/2 (ARRY-162), which is the upstream kinase that regulates ERK, inhibits ex vivo production of IL-1, TNF, and IL-6 by human whole blood after administration to healthy volunteers [48]. Similar to other MAP pathway inhibitors, however, toxicities (including skin rash and visual changes) have emerged due to the ubiquitous role of ERK. It might be more desirable to modulate, rather than block, these pathways by careful selection of pharmacokinetic profiles and judicious dosing.
Tyrosine kinases are divided into two groups. Cytoplasmic kinases transduce signals from a separate surface receptor while receptor tyrosine kinases have intrinsic tyrosine phosphorylation activity. The four Janus kinases (JAKs) are cytoplasmic tyrosine kinases that pair in at least six different combinations to integrate signaling from nearly 40 different cytokines and growth factors [49]. Cytokine receptors that comprise the common γ-chain subunit use JAK1 and JAK3 to respond to cytokines involved in RA, such as IL-6, IL-2, IL-12, or IL-15. JAKs then activate STAT proteins that translocate to the nucleus and control the expression of downstream targets.
Selective inhibitors of JAK are now in clinical studies for the treatment of RA and psoriasis [50]. The small molecule CP-690,550 inhibits JAK3, with less inhibition of JAK1 and JAK2. JAK3, which is mainly expressed in hematopoietic cells, pairs with JAK1 and signals downstream of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [49]. Initially developed as an immuno-suppressive, the compound demonstrated clinical efficacy in an early phase II trial with excellent ACR responses: CP-690,550 ACR50 33% to 54% versus placebo ACR50 6% [51]. Mechanism-based side effects were observed, including in the hematopoietic system. Neutropenia was reported at the highest dose. As a T-cell immunomodulator, this compound could have utility in a variety of autoimmune diseases assuming that the safety profile permits further development.
INCB018424, an inhibitor of JAK1, JAK2, and Tyk2 with IC50 (half inhibitory concentration) values of 2.7, 4.5, and 19 nM, respectively, is also in clinical development for RA and psoriasis. This inhibitor could indirectly affect JAK3, which needs to pair with JAK1 for most of its effects [49]. Tyk2 mediates type I IFN, IL-12, and IL-23 signaling [52]. A preliminary study that enrolled six active RA patients during 28 days showed a favorable clinical outcome without significant adverse events, using a controlled dosage to inhibit JAK1 and JAK2 but not Tyk2. The long-term safety of this powerful immunosuppressive approach must be carefully evaluated. The known complications of severe immuno-deficiency in humans bearing JAK mutations suggest that the development will need to be cautious.
Spleen tyrosine kinase (Syk) also belongs to the intracellular tyrosine kinase family. Syk is expressed in B cells, mast cells, neutrophils, macrophages, platelets, and nonhematopoietic cells, including FLS. The molecular signaling events in the Syk cascade are best defined in hematopoietic cells. Syk binds to phosphorylated activated ITAMs (immunoreceptor tyrosine-based activation motifs) that are part of immuno-receptors such as the B-cell receptor, T-cell receptor, or FcR. ITAM-Syk signaling is also triggered by integrins during cell adhesion and migration via ITAM-dependent or -independent mechanisms [53].
Less is known about Syk signaling pathways in nonhemato-poietic cells. ITAM consensus motifs are found in a number of molecules unrelated to classical immunoreceptors, and ITAM-independent mechanisms could also be engaged [54]. In synovial fibroblasts, Syk regulates the MAP kinase cascade, especially JNK-regulated genes such as IL-6 and MMP-3 [55]. Syk inhibition was able to suppress inflammation and joint destruction in a rat CIA model [56]. Treatment with tamatinib fosdium (R788), an oral Syk inhibitor, led to significant improvement in RA patients [57]. Syk is also an interesting target in SLE, in which part of the overactive T-cell phenotype is thought to be caused by the abnormal association of Syk with the T-cell receptor instead of the ζ chain Zap70. A Syk inhibitor was therapeutic and preventive in a model of murine renal lupus [58].
Imatinib mesylate was the first successful clinical application of a therapeutic designed to target tyrosine kinases. It is currently approved for several oncologic indications, including chronic myelogenous leukemia and systemic masto-cytosis. Imatinib is a potent inhibitor of platelet-derived growth factor (PDGF) receptor, c-kit (the receptor for stem cell factor, a growth factor for hematopoietic cells and mast cells), and the proto-oncogene c-Abl. Thus, the compound inhibits a spectrum of signal induction pathways relevant to inflammation and fibrosis, including PDGF signaling in synoviocytes, mast cell c-kit signaling, and TNF production by synovial fluid mononuclear cells. Imatinib is active in murine CIA, supporting its development in inflammatory arthritis [59]. Case reports indicate that it might be beneficial in refractory cases of RA, but the results of a controlled study have not been reported [60].
c-Abl also can participate in the profibrotic effects of TGF-β signaling. For instance, patients receiving imatinib for chronic myelogenous leukemia experienced marked improvement in myelofibrosis [61]. Several studies in animal models and clinical case reports in various conditions confirm that imatinib is a promising therapeutic for fibrotic disorders such as scleroderma, pulmonary fibrosis, or nephrogenic systemic fibrosis [62, 63].
Both benefits and side effects of kinase inhibitors are often observed because of structural similarities between enzymes, especially in the ATP site where most small compounds bind. Lack of selectivity might provide a therapeutic advantage in complex diseases such as RA, in which more than one molecular pathway contribute to the pathogenesis. On the other hand, it also increases the risk of side effects. Long-term studies of imatinib for the treatment of cancer patients show that severe adverse events occur in more than a third of patients, mostly within the first 2 years [64]. Therefore, careful risk-benefit analysis will be required for all of these new kinase inhibitors.
Several phosphatidylinositol 3-kinase (PI3K) inhibitors have entered clinical trials in different fields, including oncology, cardiology, and autoimmunity. Class I PI3Ks are a family of intracellular signaling proteins involved in many aspects of cell biology, including adaptive and innate immunity [65]. They are composed of heterodimers assembled from five different regulatory subunits that pair with four different catalytic subunits (α, β, γ, and δ). Activation of PI3Ks generates the key lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3). The α, β, and δ subunits are associated mainly with receptor tyrosine kinases, whereas γ subunits signal to GPCRs such as chemokine receptors. This dichotomy is not absolute and there are additional specificities depending on the cell type examined.
PI3Kα and β are expressed in most cell types, which is, in part, why cancer has been a primary drug development pathway. PI3Kδ and γ are present mainly in hematopoietic cells, suggesting that they will be better targets for therapeutic intervention in autoimmune diseases [66]. Mice lacking PI3Kγ have altered signaling in T cells, macrophages, neutrophils, and mast cells. This particular kinase is a key convergence point for many chemokine receptors. Therefore, a PI3Kγ inhibitor could potentially block chemokine function more effectively than targeting individual receptors. PI3Kδ-deficient mice have more subtle defects in neutrophil signaling and T-cell activation but have impaired B-cell functions. Interestingly, migration to the bacterial product fMLP (N-formyl-methionyl-leucyl-phenylalanine) remains intact in PI3Kδ-deficient cells while it is impaired after PI3Kγ blockade. Preclinical data show that PI3Kδ and γ inhibition can decrease the severity of arthritis either separately or in combination, the latter leading to a synergistic effect [67, 68]. In addition, PI3Kγ deficiency decreases disease activity in murine lupus models [69].
Examples of targeted therapies for rheumatic diseases
Representative molecules
Representative clinical trials
Cytokines and growth factors
IL-6 receptor
Completed phase III in RA. Phase III for sJIA.
AMG714 mAb
Insufficient efficacy in phase II (RA).
AIN457 mAb
Phase I in RA, psoriasis, and others.
Phase II for psoriatic arthritis.
Lack of efficacy in RA. Phase III in SLE.
BLyS/BAFF and APRIL
Phase I in RA.
Lack of efficacy in RA for LTβ (phase II).
B-cell targeting
Phase II in RA, SLE.
Phase II in RA.
Phase II in RA.
Phase II in SLE.
Phase II/III in SLE.
Decreased erosions in RA (phase II).
Intracellular pathways
Phase I/II in RA and transplant.
Phase II in RA.
Multiple compounds
Phase II in RA, ankylosing spondylitis, Crohn disease, and other inflammatory diseases.
PDGF-R, c-kit, c-abl
Phase II in RA and scleroderma.
Phase II in RA.
Chemokines and other GPCRs
Phase II in RA.
Adenosine A3 receptor agonist
Phase II in RA.
Ion channels
P2X7 antagonist
Phase II in RA.
American College of Rheumatology
American College of Rheumatology 20% improvement criteria
activator protein-1
a proliferation-inducing ligand
B-cell activation factor of the tumor necrosis factor family
B-lymphocyte stimulator
BAFF [B-cell activation factor of the tumor necrosis factor family] receptor 3
B- and T-lymphocyte attenuator
collagen-induced arthritis
experimental allergic encephalomyelitis
extracellular regulating kinase
fibroblast-like synoviocytes
G-protein coupled receptor
herpes virus entry mediator
inducible costimulators
immunoreceptor tyrosine-based activation motif
Janus kinase
c-Jun-N-terminal kinase
lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells
lymphotoxin beta receptor
mitogen-activated protein
matrix metalloproteinase
phosphatidylinositol 3-kinase
platelet-derived growth factor
progressive multifocal leukoencephalopathy
rheumatoid arthritis
systemic lupus erythematosus
signal transducer and activator of transcription
spleen tyrosine kinase
transmembrane activator and CAML interactor
transforming growth factor-beta
tumor necrosis factor
regulatory T cell
Supported in part by NIH grants AI067752, AI070555, and AR47825.


text: I was in Monmouth for three nights looking for property and was fortunate enough to stay at MaMere's (my mother in French). The house was built in 1891, but is well kept and very clean. Maggie went out of her way to may my stay comfortable. She and Terri made me feel right at home. I stayed in the French... More


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July 21, 2013
Position change helps Cheatham
ANAHEIM, Calif. -- Don't get Zylan Cheatham wrong. He loved his experience on the EYBL circuit with California Supreme, and he's beyond grateful for the opportunity he received this spring and summer.
But the four-star forward was tired of playing as an in-the-post center or power forward. He wants to be a wing at the next level, so he joined Arizona Magic Pump N Run to show he can be just that.
This weekend at the Double Pump Best of Summer tournament, he's proving the decision to switch teams was a fruitful one. Cheatham has been the biggest draw for college coaches this week in Anaheim, pulling in head coaches from New Mexico, San Diego State, Colorado, Arizona State and Washington, as well as assistants from many other top programs. He's played well in front of them, too.
Cheatham had probably his best day Saturday, working as more of a point forward than a power forward. He rebounded well, played with hustle and posted one of the highlights of the tournament with a poster dunk.
Next week, the NCAA world will have a better idea of where he'll take that talent.
Cheatham said he will narrow his list to 10, maybe even eight, on Friday. After that, he'll work on a list of five and try to make a decision by his birthday on Nov. 17.
"When I get down to five, that's when it's going to get busy," Cheatham said. "That's going to be my five official visits, so it's going to be busy from then on."
Cheatham said San Diego State, New Mexico, Arizona State and Washington are standing out as schools recruiting him the hardest. Lorenzo Romar, he said, has been particularly noticeable.
"Coach Romar has been at every one of my games (in the) front row," Cheatham said. "He's been in the gym before I was. He's really been picking it up. He's really showing some serious interest."
But Cheatham is far from naming a leader. His five official visits will be crucial, and finding a school that can use him as a point forward will be a huge factor.
"It's going to be tough," Cheatham said of cutting things down. "But it's something I have to do."
Court game key for Barefield
He's not the biggest guard, and as a result top 100 2015 prospect Sedrick Barefield knows he'll have to show more than his seemingly effortless scoring ability if he wants to play beyond college.
It may seem like a far-away concept for someone who has two years of high school remaining, but the generously listed 6-foot-2 Corona (Calif.) Centennial High star always has been prodigious, ahead of the curve.
"I've really been focused on just being more patient, a better facilitator," Barefield said Friday. "Scoring the ball has always been there for me and I think people thought I wasn't really a true point guard, but I've always had the vision and ability to do that. I'm just making it more of a priority now because I'm not that big, so playing the one is where I'm going to wind up, for sure."
For at least a day, Barefield had the full attention of a rapt audience of dozens of college coaches, who saw him create one basket after another for Compton Magic Select while showcasing his ample ability to fill it up from all levels.
"I'm just trying to play my game and not think so much," said Barefield, who had a great showing against standout point guard Robert Cartwright a day earlier. "I was talking to Robert a day earlier and telling him what we were going to do, and we ended up getting the win and I played good."
Barefield said he's picked up offers from Boston College, Connecticut, Kansas State, Memphis and San Diego State. He is hearing a lot from Michigan and USC and a little bit from Florida.
Fitzner plays big when needed most
Evan Fitzner will be the first to tell you he's had better weeks. Shoot, better months. But when his Pump N Run Elite squad needed him in Saturday night's closely contested open-bracket quarterfinals win over Superior Prospects, he delivered.
An unranked 6-foot-10 power forward out of Francis Parker High in San Diego, Fitzner hoped to put his best foot forward in several high-profile tournaments but instead stepped on it wrong and sprained an ankle late in a Thursday win.
Fitzner played through the ankle sprain -- which looked clearly swollen a day earlier -- and hit several second-half 3-pointers. He delivered more of a post presence on Saturday against an undersized but ultra-athletic Superior Athletes team.
"I haven't been playing my best, but I just want to keep pushing on," Fitzner said. "The first tournament wasn't very good, but I've been working on the mental part of the game and have done better this week. The ankle has bothered me some, but I'm trying to not think about it and go out there and do whatever I can to help the team win."
Fitzner has a broad skill base for a big kid, and a lot of offers have come as a result of his high ceiling. Arizona State, California, Colorado, New Mexico, Oregon State, San Diego and Washington are on the board.
Cage Jr. breaks out
The son of NBA veteran Michael Cage proved he was more than just a namesake Saturday afternoon.
Six-foot-8 Michael Cage, Jr., in fact, showed he's a big-time 2016 recruit.
The California Supreme big man, who said he's expected to grow to 6-foot-11 or 7-foot, displayed a surprising skill set for such a young post. He ran the floor well at 220 pounds, and he finished around the basket with both hands.
He even drew a huge crowd of college coaches from San Diego State, Utah, USC, Cal, Colorado and more.
"(Opponents) just kind of go at me more because they know my dad played in the NBA," Cage said after his big performance. "So they want to see what I can do by going at me. But I just give them my best."
So far Cage has one offer from SDSU, but he is hearing from UCLA, USC, Cal and Arizona as well.
He credits his early success to a lot of his father's teaching.
"He told me to play hard," Cage said. "He wasn't a star, but he always worked hard and earned his spot and started in the NBA."
Idaho shooter didn't always have skill
Utah Pump N Run advanced to the quarterfinals of the Best of Summer 16-and-under bracket behind the strong play of Malek Harwell, a 6-foot-4, 175-pound shooting guard.
Harwell is a rare Division I prospect in the respect that he's from Idaho, a state that doesn't see many prospects of his caliber.
"It's been up and down, but I've been playing well overall," Harwell said. "I've got to get my dribbling even better and play above the rim more because colleges like to see that."
Even before he hit a handful of 3-pointers in Saturday's big win, Harwell had developed a reputation on the summer circuit as a lights-out marksman. He said that has not always been the case.
"I couldn't really shoot it at first, so that's coming along very well," said Harwell, who will be a junior at Century High in Pocatello. "Defense, my footwork needs to get quicker. I used to be quick, but I've been growing so I have to get lower on those quicker guards."
Utah State was first to offer Harwell, and his games have usually had observers from the Pac-12, including Arizona State, Colorado and Stanford. Boise State and Gonzaga are also involved.
Saturday tip-ins
2016 California Supreme point guard Devearl Ramsey continued a strong summer, hitting shots from deep and displaying high-level athleticism. He said he holds an offer from USC and interest from UCLA, Cal and Arizona.
2015 Gamepoint guard Justin Simon said he's been receiving new interest from Boston College after his strong performances this past week.
2015 point guard Kahlil Simplis added an offer from New Mexico State after playing well for California Supreme.
Devin Watson, a 5-foot-10 point guard at Army and Navy Academy in Carlsbad, Calif., has performed well on a big stage in July and picked up offers from Loyola Marymount, Oregon State, San Diego and UTEP. He said Connecticut and Gonzaga are becoming more involved.
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Learning More About Estate Planning
- What is estate planning?
- What are the different types of estate planning tools?
- Why do people adopt an estate plan?
What is estate planning?
An estate plan concerns an individuals estate, which is all of the property owned by an individual, or any property in which an individual has an interest.
An estate plan concerns the management of an individuals estate during life while disabled, and the distribution of the estate at death.
What are the different types of estate planning tools?
Last Will and Testament
- A Will is a document that distributes probate assets to heirs upon death. Probate is a court proceeding in which a judge determines the validity of a Will, a personal representative collects the decedents assets and pays the bills, and then distributes property to heirs.
- Wills are useful in distributing property to heirs. If you do not have an estate plan, your estate will likely pass according to state law.
- Wills are also useful in appointing someone to act as personal representative, the person who is in charge of the estate.
- A Will is also useful to name guardians for minor children. A guardian cares for your children in the event you are deceased.
- A gift is the transfer of property to another without receiving any compensation.
- Federal gift tax is imposed on gifts of a certain amount.
- At present, you can give away up to $13,000.00 to any person, or number of persons, without tax.
- Gifted property is removed from the estate of the donor.
Powers of Attorney
- What is a power of attorney?
- A power of attorney is a document that allows another person or institution to make decisions for you in the event that you are incapacitated.
- Why do people adopt a power of attorney?
- A power of attorney allows someone to collect income, pay bills and manage assets when you are unable to do so yourself.
- Some powers of attorney allow other people to make healthcare decisions for you in the event you are incapacitated.
Why do people adopt an estate plan?
- An estate plan allows you to minimize estate and inheritance taxes.
- An estate plan will help you reduce administrative or other transfer costs.
- Estate planning allows you to distribute property to your heirs.
All of the information contained herein is for informational purposes only. The material is not intended to constitute legal, tax, investment, or financial advice and may not be used as such. Effort has been made to assure that material presented herein is accurate at time of preparation; however, this material is not intended to be a full and exhaustive explanation of the law in any area or all of the tax, investment, or financial options available. You should consult a lawyer or tax professional to insure that the same is accurate and appropriate for your unique situation. Pursuant to IRS Circular 230 you are informed that any tax information contained in this communication is not intended as tax advice and is not intended or written to be used, and cannot be used, for the purpose of (i) avoiding penalties under the Internal Revenue Code or (ii) promoting, marketing or recommending to another party any transaction or matter addressed herein.


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EVE Protomecha by JPRartWatch
©2007-2016 JPRart
Here's a new painting that I did last night. This is an homage to Liquid! graphics and one of my favorite Image books.
Let me know what you think!
Let me know what you think!
Awesome version. I got the original comics way back during release. The Liquid! coloring was amazing, and Ale Garza's art...he drew E.V.E. so cute!
Cool! I love Cyberpunk!
This piece is epic. Love it.
man that's great work!cool!
Just brilliant,like all your arts
gr8 work, love the colours here
just curious what book is the original image from?
Amazing !
straight FIYA!!!!!!!!!!!!!!!!!
My favorite.
God that is awesome and man that is an rack on her.
Lovely art, just amazing.
Bad assed!
straight up dopeness
awesome job man, I really love it, I wish I can do that stuff when I'm a bit older, guess that won't happen lol
awesome job man, I really love it, I wish I can do that stuff when I'm a bit older, guess that won't happen lol
wow gorgous... i wish i could do something like that!
love that!
love that!
this is just something else! fantastic lighting, great work
iron WOman! there i said it.
Very cute i hope you could draw like this the beautyful Psylocke
great works
great works
Looks great!
...and sexy.
...and sexy.
Not baD AT ALL...
really do like it in fact, does give me ideas on maybe alternating my style and eve-x-darkeyes.
I saw your gallery, great
eric valric
really do like it in fact, does give me ideas on maybe alternating my style and eve-x-darkeyes.
I saw your gallery, great
eric valric
Wow cool I have the favo this!!!
i LOVE eve protomecha - you did an amazing job with this, reminds a lot of the original! Liquid! graphics aint got nothing on you
Generally Sweet. I like it.
generally I like a lot it but I can see a problem with anatomy in neck/trunk area
I was watching all my favourites...and this is one of them!!!!! Take care an read my journal...I have an idea for my favs!!!!!
wow -- I didn't even see this!! What a great job! Thanks for the homage soooo much appreciated!
I was disappointed that this comic died. It had some good promise, and with a better writer and some more support, it could have been awesome.
brilliant work
Awesome image! I loved this comic series, Ale Garza is one of my favorite artists. I really hope they do a second series sometime soon! Brilliant work man!
This is amazing work.
very nice!! awesome!!
Very eye catching ......
Excelent!!!! good colors, shine, lighting...you have made one of my favorite draws in deviant!!!
Atmosphere, mood, coloring and composition, everything´s just perfect here!
Really great image-keep up the good work!
I think... hm... I think I love this one. The lighting is so beautiful. Awsome work, keep it on
I think... hm... I think I love it The lighting is astionishing.
wonderful e.v.e
Amazing, the lighting on this is absolutely stunning!
Such an amazing job you did with the details and the lighting for this pic!! I love it!!
I like the lighting effects.
..Wow. Just..wow. This is amazing. YOU'RE amazing, I'll correct myself. <3
Love the light reflexes!
Good stuff Jeremy!
sweeeeeeeeeeeeeet it is awsome
God is nice!
Loving Blue Lights!
Loving Blue Lights!
wow its amazing
Fantastic work!!!


text:
So what do YOU want for Christmas?!(214 Posts)
ThatsNotMyPinot Thu 10-Oct-13 16:00:05
Hulababy Wed 16-Oct-13 18:39:14
YukonHo Wed 16-Oct-13 00:17:59
bonnymiffy Tue 15-Oct-13 22:15:28
ArtemisatBrauron Tue 15-Oct-13 07:50:42
SugarMiceInTheRain Tue 15-Oct-13 00:36:15
YukonHo Mon 14-Oct-13 22:30:37
bonnymiffy Mon 14-Oct-13 21:35:45
SugarMiceInTheRain Mon 14-Oct-13 14:36:58
SugarMiceInTheRain Mon 14-Oct-13 12:12:23
HappyMummyOfOne Mon 14-Oct-13 11:33:20
KatyPutTheCuttleOn Mon 14-Oct-13 11:05:57
ChildrensStoriesNet Mon 14-Oct-13 09:53:10
BirdingWidow Mon 14-Oct-13 06:54:04
Mooster1709 Mon 14-Oct-13 06:11:59
BirdingWidow Mon 14-Oct-13 04:29:10
BirdingWidow Mon 14-Oct-13 04:28:22
nickstmoritz Mon 14-Oct-13 02:00:43
joanofarchitrave Mon 14-Oct-13 00:16:00
ladybirdinwaiting Mon 14-Oct-13 00:09:39
joanofarchitrave Sun 13-Oct-13 23:32:26
Runnerlegs Sun 13-Oct-13 20:00:26
ladybirdinwaiting Sun 13-Oct-13 18:55:01
gamerchick Sun 13-Oct-13 18:53:47
ladybirdinwaiting Sun 13-Oct-13 18:52:55
ladybirdinwaiting Sun 13-Oct-13 18:46:44
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It's Raining Jelly Beans
Welcome to It's Raining Jelly Beans. I have been crafty my entire life and now, more than ever, I find that I NEED to be creative. I am a dabbler- I love to dabble in all sorts of media… using all sorts of techniques… You never know what you might find in my little shop, yet no matter what I may have in my shop you can be a… read more


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John Whitgift (c. 1530 – 29 February 1604) was the Archbishop of Canterbury from 1583 to his death. Noted for his hospitality, he was somewhat ostentatious in his habits, sometimes visiting Canterbury and other towns attended by a retinue of 800 horsemen. Whitgift's theological views were often controversial.


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Ahoy there! This has been a long time coming but I figured I might as well get to it. Most have probably noticed that I don't post here terribly often and there are many reasons for that but the important thing is that I do post elsewhere. Most of my work is furry but I do still find time to draw human characters doing the whole masky suity thing. The best places to find my work that I won't be posting here are as follows:
Mostly furry work
Human mixed with furry work
therubberroom.tumblr.com/ -Mostly reblogs but some sketch work
I'm currently training as a special makeup effects artist so new work is slow coming but it is coming. I am working on coming up with scheduling that will allow me to practice class work as well as keep doing artwork.


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Mom's Strawberry Shortcake Recipe
When I was growing up, Mom sometimes experimented with different dessert recipes, but this tried-and-true spongy shortcake was always great just the way it was. It melted in my mouth! -Karen Wingate, Coldwater, Kansas
- 2 eggs
- 1-1/2 cup sugar, divided
- 1 cup all-purpose flour
- 1 teaspoon baking powder
- 1/4 teaspoon salt
- 1/2 cup 2% milk
- 1 tablespoon butter
- 1 teaspoon vanilla extract
- 1 to 1-1/2 quarts fresh strawberries, sliced
- Sweetened whipped cream
- Mint leaves, optional
- 1. Preheat oven to 350°. Grease an 8-in.-square baking pan. In a large bowl, beat eggs on medium speed 3 minutes. Gradually add 1 cup sugar, beating until thick and lemon-colored. In another bowl, whisk flour, baking powder and salt; beat into egg mixture. In a small saucepan, heat milk and butter just until butter begins to melt. Beat into batter with vanilla (batter will be thin).
- 2. Transfer batter to prepared pan. Bake 25-30 minutes or until a toothpick inserted in center comes out clean. Cool in pan 10 minutes before removing to a wire rack to cool completely.
- 3. Just before serving, cut cake into serving-size pieces; cut each slice horizontally in half. In a large bowl, combine strawberries and remaining sugar; spoon between cake layers and over top of each serving. Top with whipped cream and, if desired, mint leaves. Yield: 9 servings.
Nutritional Facts
1 serving (1 each) equals 236 calories, 3 g fat (1 g saturated fat), 52 mg cholesterol, 145 mg sodium, 49 g carbohydrate, 2 g fiber, 4 g protein.
Reviews for Mom's Strawberry Shortcake
Wine Pairings
Sweet White Wine
Enjoy this recipe with a sweet white wine such as Moscato or a sweet Riesling.
© 2016 RDA Enthusiast Brands, LLC


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Plasticville USA Bank - O&S Gauge - Original Box
- Sold for: Start Free Trial or Sign In to see what it's worth.
- Item Category: -
- Source: eBay
- Sold Date: Jun 27,2007
- Channel: Online Auction
Plasticvillle USA Bank scaled to O and S gauge. Item #1801. In original box in like new condition. Box has very minor age wear and tape on the right hand corner, but pieces are great. See our other listings for other items.


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Francois Was a Magical Horse by sebregWatch
©2014-2016 sebreg
Moral of this story? Never be more magical than a magical horse. And try to live sustainably.
Moral of the story : being sustainable is lame
A wonderful message for the children.
Why doesn't he just feed the poor croissants?
Free food? That horse is way cooler than Timmy!
is Little Timmy Peter Pan
...with croissants.
Life lesson learned


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Eddie Montalvo, New York-based conguero, is known for his rock-steady time and his ability to "lock" with other rhythm players. The pulsing beat of his playing can lure the feet of any Salsa dancer, and his work with Willie Colón, Hector Lavoe and Ruben Blades are iconic.
LP Generation II Accent Bongos feature artist-inspired designs for a look that is as dynamic as the sound.


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How do the revised rules in the Bipartisan Budget Act of 2015 affect you and your business?
Encana releases environment report
- published_in
- Today's News
The annual report, released Thursday, contains highlights of the company's efforts to achieve its corporate responsibility goals. Encana drills natural gas wells in and around the town of Erie.
"This year's report highlights significant achievements for Encana and underscores the importance we place on strong corporate governance and responsible development," Bob Grant, an Encana executive vice president, said in a statement.
Sponsor Generated Content
Bipartisan Budget Act of 2015
The report says the company has established a program to assess additives used in hydraulic fracturing operations for potential effects on human health and the environment.


text: "Today a new El Shaddai site went up on the internet. It's hard to tell exactly what we can expect from UTV Ignition, but it seems that they are working on a new project within the series. The site doesn't reveal many details, and it's in Japanese too so that makes it even harder to squeeze out the little details that are present."


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My fish love these
posted 7 years ago
My fish love this food. It is not so easy to find...petsmart does not always have it. But when they do, it is a real treat
Pros: THey love it
Cons: not so easy to find
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PlugBug gives your MacBook charger USB charging socket
If you are a mobile worker you'll know the age-old problem of finding power. Combine that with what seems to be a growing number of devices that need a regular charge and - come the end of the day - your laptop quickly starts to look like an octopus.
The problem with that, MacBook Air users will tell you, is that the MacBook air doesn't charge that quickly and doesn't charge the iPad at all, really.
In steps the PlugBug, a new gadget from Twelve South that fits on your Apple charger to give you a USB socket in which to charge your iPad or your iPhone at the same time via a more powerful wall charger.
No longer do you have to use the lacklustre USB ports on your MacBook Air, for example.
Costing $35 in the US, a UK version is due to be launched this summer and will cost £25.
Small, adaptable, and pretty clever. If you are one of those MacBook and iPad or smartphone mobile workers this might be up your street.
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text: Glitter acrylic nails ideas are some of the best choices for nail art since they can be both versatile and durable. The acrylic will last a long time and will not crack or chip within just a few days. It can last for weeks and you can even fill the gap between your growing nail and the acrylic to extend the life even further. With acrylic, it is especially important to treat your nails to maintain their health. Glitter acrylic nails ideas can make your nail art look beautiful but you need to take extra care of your nails to prevent yellowing. You can add beads to your acrylic nails but it can be a better idea to use glitter powder, which lasts even longer. The most important thing to keep in mind is how to preserve your nail health!


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text: Play-time and multi-temporality papier de conférence https://www.alexandria.unisg.ch/publications/245827 en Sub-Theme: The Temporal Experience of Organizing Steyaert, Chris Marti, Laurent Michels, Christoph 03-07-2015 2015 Steyaert, C., Marti, L., & Michels, C. (2015). Play-time and multi-temporality. In . none Entrepreneurial prototyping in the creative industries: A socio-material analysis of an avant-garde music ensemble papier de conférence https://www.alexandria.unisg.ch/publications/237625 en Marti, Laurent Steyaert, Chris 03-12-2014 2014 Marti, L., & Steyaert, C. (2014). Entrepreneurial prototyping in the creative industries: A socio-material analysis of an avant-garde music ensemble. In . none Networkings, practices, and materiality. Entrepreneurial processes in the creative industries papier de conférence https://www.alexandria.unisg.ch/publications/221275 en Marti, Laurent 13-07-2012 2012 Marti, L. (2012). Networkings, practices, and materiality. Entrepreneurial processes in the creative industries. In . 68947 Artistic Entrepreneurship : How critical can entrepreneurship be in the creative industries? papier de conférence https://www.alexandria.unisg.ch/publications/221274 en Marti, Laurent 22-11-2012 2012 Marti, L. (2012). Artistic Entrepreneurship : How critical can entrepreneurship be in the creative industries?. In Entrepreneurship and Creation of Wealth for Economies, Organisations and People. Brussels: EIASM. 68947 Rethinking 'Civil Society' via the Sociology of Flows : Crowdfunding as Spaces of Alternative Ordering? papier de conférence https://www.alexandria.unisg.ch/publications/215585 en Available conceptualizations of 'civil society' tend to depict the subject matter as a 'thing', often either credited with the potential to solve today's most pressing social problems (the progressive view) or, conversely, seen as perpetuating prevailing orders of power (the conservative view). To venture beyond these essentialist imageries which envision 'civil society' as a static configuration which is always already there, we employ the metaphor of zooming in to argue that the social is radically open, that is, neither progressive or conservative a priori but becoming progressive or conservative in the way it is enacted through heterogeneous elements. With this as a backdrop, we introduce Actor-Network Theory and After to flesh out a post-foundational understanding of the social, and use the case of crowdfunding to reflect on how technology-mediated ordering practices might bring about alternative forms of sociality. The paper concludes that Actor-Network Theory and After – despite claims to the contrary – bears critical potential in the way it pinpoints, based on empirical insights, favorable ordering practices. Dey, Pascal Marti, Laurent 11-07-2012 2012 Dey, P., & Marti, L. (2012). Rethinking 'Civil Society' via the Sociology of Flows: Crowdfunding as Spaces of Alternative Ordering?. In Democratization, Marketization, and the Third Sector, pp.1-22. Baltimore USA: International Society for Third-Sector Research ISTR. https://www.alexandria.unisg.ch/export/DL/218124.pdf none The sociology of flows as critique of capitalism: Mapping alternative flows of organizing presentazione https://www.alexandria.unisg.ch/publications/215582 en The ways in which the (re)current economic crises are enacted by academics has several important implications for the ontological politics of capitalism: first, politically inclined debates tend to polarize capitalism by essentializing it as either univocally good or bad. Second, ethical debates, which revert to higher ideals such as responsibility, justice or equality, reveal a tendency to individualize and humanize the current crises by focusing on respectively the misdeeds of concrete culprits or individual vices such as greed, self-interest, and competitiveness. Third, experts in financial affairs economize capitalism by depicting it as being primarily or exclusively a matter of (speculative) financial transactions. Though it would be wrong to assume that these perspectives are entirely misguided, they do indeed offer only a partial understanding of capitalism – particularly what concerns questions pertaining to whether capitalism can or how it should be transformed. Consequently, in this contribution, we revert to the sociology of flows to augment the critique of capitalism. To this end, we use the work of, among others, Urry, Mol, Rifkin, and Appadurai to conceptualize capitalism as a relational phenomenon constantly being (re)constituted through multiple, distributed and yet interconnected human, technical, ideological, iconic and financial flows. The sociology of flows, the argument goes, is instrumental for (a) moving away from individual-focused and systemic theories, for (b) tackling capitalism's inherent paradoxes as inter alia materialized in its dialectic of flow and closure, homogeneity and heterogeneity, and for (c) grasping its material disjunctures (e.g. socio-economic inequalities). Whilst suggesting that academic theorizing of capitalism needs to be expanded beyond economic operations, we move to the peripheries of the capitalist fabric so as to address the possibility of "alternatives". Conceptualizing "alternatives" as socio-material (re)assemblings performed by communities-of-alternative-practices, we illustrate our deliberations through cases which transgress the status quo by inventing novel flows, by re-appropriating existing flows, or by combining existing flows in unprecedented ways. Marti, Laurent Dey, Pascal 10-02-2012 2012 Marti, L., & Dey, P. (2012). The sociology of flows as critique of capitalism: Mapping alternative flows of organizing. Presented at Designing and Transforming Capitalism Conference, Aarhus, Denmark. none Multiplicity and reflexivity in organizational research : Towards a performative approach to the visual Journal paper https://www.alexandria.unisg.ch/publications/214817 en urn:ISSN:1746-5648 doi:10.1108/17465641211223456 Qualitative Research in Organizations and Management: An International Journal Purpose – The purpose of this paper is, first, to assess the potential of the visual to enact multiplicity and reflexivity in organizational research, and second, to develop a performative approach to the visual, which offers aesthetic strategies for creating future research accounts in organization and management studies. Design/methodology/approach – The paper reviews existing visual research in organization and management studies and presents an in-depth analysis of two early, almost classical, and yet very different endeavors to create visual accounts based on ethnography: the multi-media enactments by Bruno Latour, Emilie Hermant, Susanna Shannon, and Patricia Reed, and the filmic and written work by Trinh T. Minh-ha and her collaborators. Findings – The authors' analysis of how the visual is performed in both cases identifies a repertoire of three distinct and paradoxical aesthetic strategies: de/synchronizing, de/centralizing, and dis/covering. Originality/value – The authors analyze two rarely acknowledged but ground-breaking research presentations, identify aesthetic strategies to perform multiplicity and reflexivity in research accounts, and question the ways that research accounts are written and published in organization and management studies by acknowledging the consequences of a performative approach to the visual. Aesthetics, Bruno Latour, Management, Multiplicity, Organizations, Performative approach, Reflexivity, Trinh T. Minh-ha, Visual methods, Visualization Steyaert, Chris Marti, Laurent Michels, Christoph 0-07-2012 2012 Steyaert, C., Marti, L., & Michels, C. (2012). Multiplicity and reflexivity in organizational research: Towards a performative approach to the visual. Qualitative Research in Organizations and Management: An International Journal, 7(01/2012), 34-53, DOI:10.1108/17465641211223456. none Enacting ethnography: multiplying the organization presentazione https://www.alexandria.unisg.ch/publications/70118 en Michels, Christoph Marti, Laurent 28-06-2010 2010 Michels, C., & Marti, L. (2010). Enacting ethnography: multiplying the organization. Presented at 26th EGOS Colloquium, Lissabon, Portugal. none Actor-Network Theory in Design Research capitolo libro https://www.alexandria.unisg.ch/publications/74826 en Scheuermann, Arne Mareis, Claudia Marti, Laurent 2009 2009 Scheuermann, A., Mareis, C., & Marti, L. (2009). Actor-Network Theory in Design Research. In Multiple Ways to Design Research. Research cases that reshape the design discipline. (pp. 67): Swiss Design Network. 68947


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I enjoyed tour.. The guide was very informative, courtesy and his knowledge was great..
lots of interesting details...
details that just going into museum on your own you would not have heard..
thisis my second tour with Viator and i would highly recommend to others and will in future trip book other other tours with Viator.. thank you
This is a wonderful tour in my opinion. I love La Scala and was fascinated by the history that the guide provided. The museum is full of interesting memorabilia, much of which is also explained during the tour. I highly recommend this tour and will consider taking it again next year when I am in Milan.
The tour was excellent.The guide was absolutely terrific. We had no idea that the tour would be so good. The guide was very informative, interesting and certainly knew his history. We got to see the cast of Aida rehearsing. We saw the complete stage area with the scenery drapes hoisted and let down.We saw the stage raised by hydraulics. We spent as much time as we wanted in one of the boxes in the auditorium. Brilliant! Would highly recommend it.
We had a great tour of La Scala and the museum. Our guide was extremely knowledgable and spoke very good English. We were able to look down into the seating area and hear a little during a rehearsal for a performance that night. The museum has some very interesting artifacts and photos, which we really enjoyed. Altogether, a highly recommended tour.
The tour was extremely interesting and informative. Getting to see part of a full orchestra rehearsal was a special treat. Our guide was very knowledgeable and answered many questions from those of us on the tour. I highly recommend this tour.
It wad great!!!
Maria Ines P Uruguay
Very nice and interesting tour. Thank you.
Very complete tour. The guide was great. We enjoyed it very much.
Merrilyn E Australia
As a classical music/opera lover, I thoroughly enjoyed the La Scala tour. The museum has many historical music instruments, photos and artefacts. The theatre is amazing. The guide gave an interesting and comprehensive coverage of the history of the building, featured composers, artists, etc.
Definitely a must see for anyone interested in opera,and a very good guide who was very knowledgeable who said her grandfather used to sit in the top row of scala.You will have to do the tour to understand the relevance of the last comment.Cant recommend highly enough this tour.
JUDDY United Kingdom
I really enjoyed my visit to La Scala. The guide was so helpful especially when one of my party was late arriving. She told the office of the late arrival and my friend was able to join us when she arrived. We were given so much interesting information and were taken into one of the boxes so we could see the auditorium. The interior of the theatre is magnificent.
The tour guide was absolutely excellent. Very informative and very unstuffy and funny as well. Would have liked to have seen more of the actual theatre as the tour does not take you back stage but the tour guide was worth the money we paid.
Very interesting and informative.
Our guide was wonderful. Very thorough and knowledgeable and paced the visit well. We were able to peek inside the actual performance area of the theater even though there was a full dress rehearsal going on, so it was great to be able to see the sound and light crew at work, the full orchestra performing, and the artists on stage singing. Of course it would be nice to be inside and get the full-on La Scala submersion, but if you want that, you'll need to buy a ticket to a performance! Our guide also gave us access to the area just outside the entry doors where only private parties are held now, so we were able to take photos with busts of many famous composers. Her guided tour of the museum was well worthwhile as she explained many details you would miss seeing it on your own. We applaud her stamina and patience with the group. Well worth the price!
Terrific tour
Really enjoyed it! :)
A very interesting tour that was really worthwhile. Our guide was very friendly and charming and had loads of interesting facts to tell. The Scala itself is stunning especially when you are standing in one of the red boxes looking down on the stage.
The Scala tour was a lovely and elegant experience, with the most interesting explanations from our tour guide and lovely music. It is a must for anyone going to Milan!
The tour was really good and I'd recommend it to anyone. The tour guide Alessandro is a very good communicator and gave us lots of information including stories about people and other things that had played an interesting and significant role in the history of La Scala. He was able to answer all our questions. You just can't easily get this type of information from books or by just looking. The tour gave a whole depth of perspective in such a short time. Everything was well organised including the frequent reminders to bring the booking confirmation.
Bill Canada
This was a great tour. We were able to gain access to the theatre in ways that I don' t believe we could otherwise attain. The guide was very informative and provided us with added value with extra bits of information on the history and construction of the theatre. Highly recommend.
Thank you for helping fulfill one of my travel dreams-visiting La Scala. While I couldn't afford a ticket to one of the operas, your tour made me connect closely with the lovely house. Our tour guide had great poise and lots of great info. If you love opera, you will thoroughly enjoy this tour.
I enjoyed my trip to Milan but I never got to La Scala because I had my purse and phone taken by a pickpocket on the metro station on my way there so spent the morning sorting things out and having to go to the Police station. There's always another time!! My friends thought it very good
very enjoyable tour the tour guide was great.
our tour of the Opera House was excellent-I highly recommend booking-the tour was made exceptionaly good due to the passionate and informed guide......


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Kise Ryota by twinfoolsWatch
©2014-2016 twinfools
OH MY GOD, I LOVE YOU'RE COSPLAYS SO MUCH!!!! ^//w//^
I like your cosplay, but God dang it you make me feel ugly. <.>
It's so pretty *^*
How handsome! *o*
perfect cosplay and awesome dude !
Awesome cosplay! I wanna 1v1 you haha
It whould be awfully awesome if I could photograph you one of these days!! I see your new postings all the time, I think it is neat you are so committed to cosplay & I can see why you have so many loyal fans!
Reason? Because you care deeply with your craft...!
Hey I think this one looks better than the other Kise shot ! Really nice ! *u*
That is a really good shoot. You look so good.
So Handsome!!!
So awesome!
cool!! <33
Oh wow that is NICE <3
My brain processed this as a drawing at first and I was like "Twin drew something what omg" and then I saw a cosplay and I was like "WHAT JUST HAPPENED TO MY MIND?"
God whatever. I'm watching Sharknado, I'm going to blame everything on this horrible movie.
God whatever. I'm watching Sharknado, I'm going to blame everything on this horrible movie.
Your cosplays continue to amaze me and everyone else! ^-^
Kise-kun :3
amazing shot. saving the best for last
Beautiful photo and great cosplay!
Awesome Photo. C:
Winwinwinwinwinwinwinwinwin WINNING!!! Omg, you are too great!!


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i loved that game so simple an so good
waw ftw best cod ever were the BETTER player win
Except the mp-40 and juggernaut, and betties. It was a great game.
because then you and everybody else would complain they didnt change enough, same ol call of duty blah blah, you cant please everybody.
i hate wwII era games. seen all the weapons and tech. nothing to look forward to, imo. i personally will never buy another one in my life.


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Update on JivanJivan was born in 1961 in the town of Kadjaran. After high school, he graduated from Kapan Polytechnic Institute with a specialty in mining engineering. Jivan has three daughters and a son.
The eldest daughter is 23 and is studying in the third year at Yerevan Medical University in the therapeutic department. The middle daughter is 20 and is studying in the second year at Kapan Polytechnic Institute in the finance-economics department. Jivan's youngest daughter is 19 and is studying in the second year at Yerevan Medical University in the therapeutic department. Jivan's wife is a homemaker.
Since 1997, Jivan has been engaged in his own territory in the business of manufacturing commercial vehicle bodies, and he has his own equipment, a lifting crane, and a loading machine.
Jivan needs a loan of 900,000 Armenian drams to pay for the education of his daughters for a semester.
С 1997года Дживан занимается на своей территории предпринимательской деятельностью изготовлением кузова для грузовых автомобилей, имеет собственное оборудование, подъемный автокран, погрузочную машину.
Дживану нужен кредит на сумму 900.000 Армянских драм для оплаты за обучение своих дочерей за семестр.
Previous Loan DetailsJivan was born in 1961 in the town of Kajaran. After graduating from Kapan high school, he enrolled in the Kapan branch of the Yerevan Polytechnic Institute, where he received a degree as an engineer-miner. Jivan is married and has four children: three daughters and a son. His daughters are un... More from Jivan's previous loan »
Additional Information
More information about this loan
This loan is part of NorHorizon's education program, designed to finance school tuition for students whose families have low incomes or work in informal sectors of the economy. Funds can be used for partial or complete payment of expenses related to higher education. By supporting this loan, you're enabling access to education for students with limited options.
About "Nor Horizon"
"Nor Horizon" UCO LLC is committed to promoting poverty alleviation in Armenia by providing high-quality financial and other business development services to enterprising individuals in under-served rural and urban markets who have a strong will to establish and develop their own small-scale businesses. Originally created as the Armenian micro credit program of Oxfam (Great Britain) in late 1995, "Nor Horizon" LLC has been licensed under supervision of the Central Bank of Armenia since early 2006.
For more information about "Nor Horizon," please visit the partner page or website.
To stay updated on loans from Armenia, please join the Armenia lending team at http://www.kiva.org/team/armenia.
Concurrent and Successive Loans
Our Field Partners often work with borrowers over a series of loans as the borrowers build credit, take out bigger loans, and expand their businesses. In order to make it easier for our Field Partners to post loans for borrowers who have been listed on Kiva before, we allow them to post successive and concurrent loans for their Kiva borrowers. This means that our Field Partners are able to post a borrower's second, third, etc., loan on Kiva without having to re-enter all of the borrower's information.
This borrower has been listed on Kiva before, so you'll see an updated loan description, as well as excerpts of the original descriptions from earlier loans. Most borrowers take out loans consecutively, meaning that they receive a second loan after having repaid the first. However, sometimes our Field Partners give out concurrent loans, allowing borrowers to take out one primary loan and a secondary "add-on" loan along with it. These "add-on" loans are typically smaller than the borrower's primary loan and serve a different purpose. Because Field Partners can now post loans as successive and concurrent loans, you will be able to track borrower progress over time and see the various ways a borrower is working with our Field Partners through funds from Kiva's lenders.
About Armenia
154View loans »
Success!! The loan was 100% repaid
- Repayment Term
- 20 months (Additional Information)
- Repayment Schedule
- Monthly
- Pre-Disbursed:
- Mar 6, 2013
- Listed
- Mar 29, 2013
- Currency Exchange Loss:
- Possible
- Ended:
- Oct 17, 2014