The CLIVAR C20C Project: Which components of the Asian-Australian monsoon circulation variations are forced and reproducible?

A multi-model set of atmospheric simulations forced by historical sea surface temperature (SST) or SSTs plus Greenhouse gases and aerosol forcing agents for the period of 1950-1999 is studied to identify and understand which components of the Asian-Australian monsoon (A-AM) variability are forced and reproducible. The analysis focuses on the summertime monsoon circulations, comparing model results against the observations. The priority of different components of the A-AM circulations in terms of reproducibility is evaluated. Among the subsystems of the wide A-AM, the South Asian monsoon and the Australian monsoon circulations are better reproduced than the others, indicating they are forced and well modeled. The primary driving mechanism comes from the tropical Pacific. The western North Pacific monsoon circulation is also forced and well modeled except with a slightly lower reproducibility due to its delayed response to the eastern tropical Pacific forcing. The simultaneous driving comes from the western Pacific surrounding the maritime continent region. The Indian monsoon circulation has a moderate reproducibility, partly due to its weakened connection to June-July-August SSTs in the equatorial eastern Pacific in recent decades. Among the A-AM subsystems, the East Asian summer monsoon has the lowest reproducibility and is poorly modeled. This is mainly due to the failure of specifying historical SST in capturing the zonal land-sea thermal contrast change across the East Asia. The prescribed tropical Indian Ocean SST changes partly reproduce the meridional wind change over East Asia in several models. For all the A-AM subsystem circulation indices, generally the MME is always the best except for the Indian monsoon and East Asian monsoon circulation indices

The CLIVAR C20C Project: Which components of the Asian-Australian monsoon circulation variations are forced and reproducible?

A multi-model set of atmospheric simulations forced by historical sea surface temperature (SST) or SSTs plus Greenhouse gases and aerosol forcing agents for the period of 1950–1999 is studied to identify and understand which components of the Asian–Australian monsoon (A–AM) variability are forced and reproducible. The analysis focuses on the summertime monsoon circulations, comparing model results against the observations. The priority of different components of the A–AM circulations in terms of reproducibility is evaluated. Among the subsystems of the wide A–AM, the South Asian monsoon and the Australian monsoon circulations are better reproduced than the others, indicating they are forced and well modeled. The primary driving mechanism comes from the tropical Pacific. The western North Pacific monsoon circulation is also forced and well modeled except with a slightly lower reproducibility due to its delayed response to the eastern tropical Pacific forcing. The simultaneous driving comes from the western Pacific surrounding the maritime continent region. The Indian monsoon circulation has a moderate reproducibility, partly due to its weakened connection to June–July–August SSTs in the equatorial eastern Pacific in recent decades. Among the A–AM subsystems, the East Asian summer monsoon has the lowest reproducibility and is poorly modeled. This is mainly due to the failure of specifying historical SST in capturing the zonal land-sea thermal contrast change across the East Asia. The prescribed tropical Indian Ocean SST changes partly reproduce the meridional wind change over East Asia in several models. For all the A–AM subsystem circulation indices, generally the MME is always the best except for the Indian monsoon and East Asian monsoon circulation indices

The CLIVAR C20C Project: Which components of the Asian-Australian monsoon circulation variations are forced and reproducible?

A multi-model set of atmospheric simulations forced by historical sea surface temperature (SST) or SSTs plus Greenhouse gases and aerosol forcing agents for the period of 1950-1999 is studied to identify and understand which components of the Asian-Australian monsoon (A-AM) variability are forced and reproducible. The analysis focuses on the summertime monsoon circulations, comparing model results against the observations. The priority of different components of the A-AM circulations in terms of reproducibility is evaluated. Among the subsystems of the wide A-AM, the South Asian monsoon and the Australian monsoon circulations are better reproduced than the others, indicating they are forced and well modeled. The primary driving mechanism comes from the tropical Pacific. The western North Pacific monsoon circulation is also forced and well modeled except with a slightly lower reproducibility due to its delayed response to the eastern tropical Pacific forcing. The simultaneous driving comes from the western Pacific surrounding the maritime continent region. The Indian monsoon circulation has a moderate reproducibility, partly due to its weakened connection to June-July-August SSTs in the equatorial eastern Pacific in recent decades. Among the A-AM subsystems, the East Asian summer monsoon has the lowest reproducibility and is poorly modeled. This is mainly due to the failure of specifying historical SST in capturing the zonal land-sea thermal contrast change across the East Asia. The prescribed tropical Indian Ocean SST changes partly reproduce the meridional wind change over East Asia in several models. For all the A-AM subsystem circulation indices, generally the MME is always the best except for the Indian monsoon and East Asian monsoon circulation indices.Submitted3.7. Dinamica del clima e dell'oceanoJCR Journalope

Suppression of HIV-Specific and Allogeneic T Cell Activation by Human Regulatory T Cells Is Dependent on the Strength of Signals

Regulatory T cells (Tregs) suppress immune responses against both self and non-self antigens. Tregs require activation through the T cell receptor (TCR) and IL-2 to exert their suppressive functions. However, how strength of TCR signals modulate the potency of Treg-mediated suppression of antigen-specific T cell activation remain unclear. We found that both strength of TCR signals and ratios of Tregs to target cells, either through superantigen, allogeneic antigens or HIV-specific peptides, modified the suppressive ability of Tregs. While human Tregs were able to mediate suppression in the presence of only autologous antigen-presenting cells, this was much less efficient as compared to when Tregs were activated by allogeneic dendritic cells. In another physiologically relevant system, we show that the strength of peptide stimulation, high frequency of responder CD8+ T cells or presence of high IL-2 can override the suppression of HIV-specific CD8+ T cells by Tregs. These findings suggest that ratios and TCR activation of human Tregs, are important parameters to overcome robust immune responses to pathogens or allogeneic antigens. Modulating the strength of T cell signals and selective enhancement or depletion of antigen-specific Tregs thus may have implications for designing potent vaccines and regulating immune responses during allogeneic transplantation and chronic infections

Dysfunction of Nrf-2 in CF Epithelia Leads to Excess Intracellular H2O2 and Inflammatory Cytokine Production

Cystic fibrosis is characterized by recurring pulmonary exacerbations that lead to the deterioration of lung function and eventual lung failure. Excessive inflammatory responses by airway epithelia have been linked to the overproduction of the inflammatory cytokine IL-6 and IL-8. The mechanism by which this occurs is not fully understood, but normal IL-1β mediated activation of the production of these cytokines occurs via H2O2 dependent signaling. Therefore, we speculated that CFTR dysfunction causes alterations in the regulation of steady state H2O2. We found significantly elevated levels of H2O2 in three cultured epithelial cell models of CF, one primary and two immortalized. Increases in H2O2 heavily contributed to the excessive IL-6 and IL-8 production in CF epithelia. Proteomic analysis of three in vitro and two in vivo models revealed a decrease in antioxidant proteins that regulate H2O2 processing, by ≥2 fold in CF vs. matched normal controls. When cells are stimulated, differential expression in CF versus normal is enhanced; corresponding to an increase in H2O2 mediated production of IL-6 and IL-8. The cause of this redox imbalance is a decrease by ∼70% in CF cells versus normal in the expression and activity of the transcription factor Nrf-2. Inhibition of CFTR function in normal cells produced this phenotype, while N-acetyl cysteine, selenium, an activator of Nrf-2, and the overexpression of Nrf-2 all normalized H2O2 processing and decreased IL-6 and IL-8 to normal levels, in CF cells. We conclude that a paradoxical decrease in Nrf-2 driven antioxidant responses in CF epithelia results in an increase in steady state H2O2, which in turn contributes to the overproduction of the pro-inflammatory cytokines IL-6 and IL-8. Treatment with antioxidants can ameliorate exaggerated cytokine production without affecting normal responses

Resting Regulatory CD4 T Cells: A Site of HIV Persistence in Patients on Long-Term Effective Antiretroviral Therapy

BACKGROUND: In HIV-infected patients on long-term HAART, virus persistence in resting long-lived CD4 T cells is a major barrier to curing the infection. Cell quiescence, by favouring HIV latency, reduces the risk of recognition and cell destruction by cytotoxic lymphocytes. Several cell-activation-based approaches have been proposed to disrupt cell quiescence and then virus latency, but these approaches have not eradicated the virus. CD4+CD25+ regulatory T cells (Tregs) are a CD4+ T-cell subset with particular activation properties. We investigated the role of these cells in virus persistence in patients on long-term HAART. METHODOLOGY/PRINCIPAL FINDINGS: We found evidence of infection of resting Tregs (HLADR(-)CD69(-)CD25(hi)FoxP3+CD4+ T cells) purified from patients on prolonged HAART. HIV DNA harbouring cells appear more abundant in the Treg subset than in non-Tregs. The half-life of the Treg reservoir was estimated at 20 months. Since Tregs from patients on prolonged HAART showed hyporesponsiveness to cell activation and inhibition of HIV-specific cytotoxic T lymphocyte-related functions upon activation, therapeutics targeting cell quiescence to induce virus expression may not be appropriate for purging the Treg reservoir. CONCLUSIONS: Our results identify Tregs as a particular compartment within the latent reservoir that may require a specific approach for its purging

Identifying and prioritizing strategies for comprehensive liver cancer control in Asia

<p>Abstract</p> <p>Background</p> <p>Liver cancer is both common and burdensome in Asia. Effective liver cancer control, however, is hindered by a complex etiology and a lack of coordination across clinical disciplines. We sought to identify strategies for inclusion in a comprehensive liver cancer control for Asia and to compare qualitative and quantitative methods for prioritization.</p> <p>Methods</p> <p>Qualitative interviews (N = 20) with international liver cancer experts were used to identify strategies using Interpretative Phenomenological Analysis and to formulate an initial prioritization through frequency analysis. Conjoint analysis, a quantitative stated-preference method, was then applied among Asian liver cancer experts (N = 20) who completed 12 choice tasks that divided these strategies into two mutually exclusive and exhaustive subsets. Respondents' preferred plan was the primary outcome in a choice model, estimated using ordinary least squares (OLS) and logistic regression. Priorities were then compared using Spearman's Rho.</p> <p>Results</p> <p>Eleven strategies were identified: <it>Access to treatments; Centers of excellence; Clinical education; Measuring social burden; Monitoring of at-risk populations; Multidisciplinary management; National guidelines; Public awareness; Research infrastructure; Risk-assessment and referral</it>; and <it>Transplantation infrastructure</it>. Qualitative frequency analysis indicated that <it>Risk-assessment and referral </it>(85%), <it>National guidelines </it>(80%) and <it>Monitoring of at-risk populations </it>(80%) received the highest priority, while conjoint analysis pointed to <it>Monitoring of at-risk populations </it>(p < 0.001), <it>Centers of excellence </it>(p = 0.002), and <it>Access to treatments </it>(p = 0.004) as priorities, while <it>Risk-assessment and referral </it>was the lowest priority (p = 0.645). We find moderate concordance between the qualitative and quantitative methods (rho = 0.20), albeit insignificant (p = 0.554), and a strong concordance between the OLS and logistic regressions (rho = 0.979; p < 0.0001).</p> <p>Conclusions</p> <p>Identified strategies can be conceptualized as the ABCs of comprehensive liver cancer control as they focus on <it>Antecedents</it>, <it>Better care </it>and <it>Connections </it>within a national strategy. Some concordance was found between the qualitative and quantitative methods (e.g. <it>Monitoring of at-risk populations</it>), but substantial differences were also identified (e.g. qualitative methods gave highest priority to risk-assessment and referral, but it was the lowest for the quantitative methods), which may be attributed to differences between the methods and study populations, and potential framing effects in choice tasks. Continued research will provide more generalizable estimates of priorities and account for variation across stakeholders and countries.</p

Relationship between Regulatory T Cells and Immune Activation in Human Immunodeficiency Virus-Infected Patients Interrupting Antiretroviral Therapy

Persistent immune activation plays a central role in driving Human Immunodeficiency Virus (HIV) disease progression. Whether CD4+CD25+ regulatory T cells (Tregs) are harmful by suppressing HIV-specific immune responses and/or beneficial through a decrease in immune activation remains debatable. We analysed the relationship between proportion and number of regulatory T cells (Tregs) and immune activation in HIV-infected patients interrupting an effective antiretroviral therapy (ART). Twenty-five patients were included in a substudy of a prospective multicenter trial of treatment interruption (TI) (ANRS 116). Proportions and numbers of Tregs and the proportion of activated CD4 and CD8 T cells were assessed at baseline and month 12 (M12) of TI. Specific anti-HIV CD4 and CD8 responses were investigated at baseline and M12. Non parametric univariate analyses and multivariate linear regression models were conducted. At baseline, the proportion of Tregs negatively correlated with the proportion of HLA-DR+CD8+T cells (r = −0.519). Following TI, the proportion of Tregs increased from 6.3% to 7.2% (p = 0.029); absolute numbers of Tregs decreased. The increase in the proportion of HLA-DR+CD38+CD8+T cells was significantly related to the increase in proportion of Tregs (p = 0.031). At M12, the proportion of Tregs did not negatively correlate with CD8 T-cell activation. Nevertheless, Tregs retain a suppressive function since depletion of Treg-containing CD4+CD25+ cells led to an increase in lymphoproliferative responses in most patients studied. Our data suggest that Tregs are efficient in controlling residual immune activation in patients with ART-mediated viral suppression. However, the insufficient increase in the proportion and/or the decrease in the absolute number of Tregs result in a failure to control immune activation following TI