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Suppression of an excessive systemic inflammatory response is a promising and potent strategy for treating endotoxic sepsis. Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan catabolism, may play a critical role in various inflammatory disorders. In this study, we report a critical role for IDO in the dysregulated immune response associated with endotoxin shock. We found that IDO knockout (IDO ؊/؊ ) mice and 1-methyl-D-tryptophan-treated, endotoxin-shocked mice had decreased levels of the cytokines, TNF-␣, IL-6, and IL-12, and enhanced levels of IL-10. Blockade of IDO is thought to promote host survival in LPS-induced endotoxin shock, yet little is known about the molecular mechanisms that regulate IDO expression during endotoxin shock. In vitro and in vivo, IDO expression was increased by exogenous IL-12, but decreased by exogenous IL-10 in dendritic cells and splenic dendritic cells. Interestingly, whereas LPS-induced IL-12 levels in serum were higher than those of IL-10, the balance between serum IL-12 and IL-10 following challenge became reversed in IDO Sepsis is a systemic inflammatory response syndrome induced by microbial infection that is characterized by hemodynamic shock and multiple organ failure (1, 2). The pathogenesis of sepsis involves a progressive and dynamic expansion of a systemic inflammatory response to bacterial infection (3). Endotoxin, or LPS, is a major component of the outer membrane of Gram-negative bacteria; as such, it is an effective trigger of the inflammatory response during infection with Gram-negative bacteria. Uncontrolled activation of LPS-induced mechanisms results in sepsis. However, growing evidence supports the idea that LPS does not directly cause septic shock and tissue injury. Rather, it stimulates the production of proinflammatory cytokines, such as TNF-␣ and IL-1␤, which, in the context of massive infections associated with sepsis, can precipitate tissue injury and lethal shock (1, 4). It is a major cause of morbidity and mortality in hospitalized patients, yet effective treatment modalities remain elusive. Sepsis is associated with acute and systemic host immune responses; in the case of cell-mediated immune responses, the release of cytokines, such as TNF-␣, IL-1␤, IL-6, IL-12p70, and IFN-␥, is mechanistically involved in sepsis development (5). Immune and inflammatory systems are controlled by multiple proand anti-inflammatory cytokines, many of which are absent under normal, homeostatic conditions. However, massive bacterial infections cause the host to produce excessive amounts of proinflammatory cytokines that threaten the host's survival (6). Thus, the balance between proinflammatory and anti-inflammatory influences is likely a critical element in the mechanism of sepsis.Dendritic cells (DCs) 3 are potent APCs and provide costimulatory signals for innate and adaptive immune responses. For example, LPS promotes DC maturation and IL-12 secretion, which primes naive CD4 T cell toward a Th1 phenotype (7). In contrast, IL-10 produc...

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-␥ (IFN␥)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme inT-cell suppression-mediated immune tolerance to tumors. STAT1 phosphorylation appears to play an important role in the control of IDO expression by IFN␥, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFN␥-induced IDO expression in bone marrow-derived dendritic cells. In addition, we demonstrate that curcumin, an active component of turmeric, significantly inhibited the induction of IDO expression and activity by IFN␥. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase C␦ phosphorylation in bone marrow-derived DCs, suppressing the subsequent translocation and binding of STAT1 to the GAS element of the IRF-1 promoter. Coincident with these inhibitory effects on IFN␥-induced IDO expression, curcumin reversed IDO-mediated suppression of T-cell responses. Our results, thus, suggest that down-regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers.Dendritic cells (DCs) 3 are professional antigen-presenting cells that function as immune sentinels for the initiation of T-cell responses against microbial pathogens and tumors (1, 2). It is now well known that DCs not only induce immunity but are also important for the induction of T-cell tolerance. In particular, murine CD11c ϩ DCs that coexpress the markers CD8␣, B220, DX5, and DEC205 promote tolerance rather than immunity to specific antigens (3, 4). One of the mechanisms that might contribute to this tolerance in antigen-presenting cells involves the expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO).IDO catalyzes the initial and rate-limiting step in the catabolism of tryptophan along the kynurenine pathway. IDO has also recently been established as a key enzyme in T-cell suppression and the induction of immune tolerance (5-7). The expression of IDO by various cell types has broad immunological significance. In particular, in many tumors and tolerant antigen-presenting cells, IDO degrades tryptophan to kynurenine, leading to the depletion of tryptophan and resulting in the suppression of T-cell proliferation (8 -10). Recent in vivo studies suggest that IDO-expressing DCs isolated from tumordraining lymph nodes contribute to the progression of tumors by creating local immunosuppression (11-13).The control of IDO transcription is complex and cell typespecific (6). A number of pathways, including the mitogen-activated protein kinase and noncanonical NF-B signaling pathways as well as the Janus-activated kinase-signal transducer and activator of transcription (JAK-STAT) pathway, can modulate IDO expression in response to a variety of stimuli (14,15). In macrophages and DCs, transcription of the IDO gene is s...

[1] It is known that General Circulation Models (GCMs) have insufficient resolution to accurately simulate hurricane near-eye structure and intensity. The increasing capabilities of high-end computers have changed this. The mesoscaleresolving finite-volume GCM (fvGCM) has been experimentally deployed on the NASA Columbia supercomputer, and its performance is evaluated in this study by choosing hurricane Katrina as an example. In late August 2005, Katrina underwent two stages of rapid intensification, and became the sixth most intense hurricane in the Atlantic. Six 5-day simulations of Katrina at both 0.25°and 0.125°show comparable track forecasts but the 0.125°runs provide much better intensity forecasts, producing the center pressure with errors of only ±12 hPa. In the runs examined in this study, the 0.125°simulates better near-eye wind distributions and a more realistic average intensification rate. To contribute to the ongoing research on the effects of disabling convection parameterization (CP), we present promising results by comparing 0.125°runs with disabled CPs against runs with enabled CPs.

New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C5-NH2) > F (C5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C5-NH2) > naphthyridine = F (C5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (microgram/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Actinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.

The NASA Columbia supercomputer was ranked second on the TOP500 List in November, 2004. Such a quantum jump in computing power provides unprecedented opportunities to conduct ultra‐high resolution simulations with the finite‐volume General Circulation Model (fvGCM). During 2004, the model was run in realtime experimentally at 0.25 degree resolution producing remarkable hurricane forecasts (Atlas et al., 2005). In 2005, the horizontal resolution was further doubled, which makes the fvGCM comparable to the first mesoscale resolving General Circulation Model at the Earth Simulator Center (Ohfuchi et al., 2004). Nine 5‐day 0.125 degree simulations of three hurricanes in 2004 are presented first for model validation. Then it is shown how the model can simulate the formation of the Catalina eddies and Hawaiian lee vortices, which are generated by the interaction of the synoptic‐scale flow with surface forcing, and have never been reproduced in a GCM before.

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