SummaryThe integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled nonrepressed (GCN2) kinase is a key orchestrator of the ISR, and modulates cellular metabolism in response to amino acid starvation. Here we demonstrate that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of GCN2 in CD11c+ APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and Th17 responses, due to enhanced inflammasome activation and IL-1β production. This was caused by reduced autophagy in GCN2−/− intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes1. Thus, conditional ablation of Atg5 and Atg7 in intestinal APCs resulted in enhanced ROS and Th17 responses. Furthermore, in vivo blockade of ROS and IL-1β resulted in inhibition of Th17 responses and reduced inflammation in GCN2−/− mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.

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In this manuscript we use an exactly solvable stochastic binary model for regulation of gene expression to analyse the dynamics of response to a treatment aiming to modulate the number of transcripts of RKIP gene. We demonstrate the usefulness of our method simulating three treatment scenarios aiming to reestablish RKIP gene expression dynamics towards pre-cancerous state: i. to increase the promoter’s ON state duration; ii. to increase the mRNAs’ synthesis rate; iii. to increase both rates. We show that the pre-treatment kinetic rates of ON and OFF promoter switching speeds and mRNA synthesis and degradation will affect the heterogeneity and time for treatment response. Hence, we present a strategy for reducing drug dosage by simultaneously targeting multiple kinetic rates. That enables a reduction of treatment response time and heterogeneity which in principle diminishes the chances of emergence of resistance to treatment. This approach may be useful for inferring kinetic constants related to expression of antimetastatic genes or oncogenes and on the design of multi-drug therapeutic strategies targeting master regulatory genes.

In spite of several decades of research, an effective vaccine against schistosomiasis remains elusive. The radiation-attenuated (RA) cercarial vaccine is still the best model eliciting high protection levels, although the immune mechanisms have not yet been fully characterized. In order to identify genes and pathways underlying protection we investigated patterns of gene expression in PBMC and skin draining Lymph Nodes (LN) from mice using two exposure comparisons: vaccination with 500 attenuated cercariae versus infection with 500 normal cercariae; one versus three doses. Vaccinated mice were challenged with 120 normal parasites. Integration of PBMC and LN data from the infected group revealed early up-regulation of pathways associated with Th2 skewing and polarization of IgG antibody profiles. Additionally, hemostasis pathways were downregulated in infected mice, correlating with platelet reduction, potentially a mechanism to assist parasite migration through capillary beds. Conversely, up regulation of such mechanisms after vaccination may explain parasite blockade in the lungs. In contrast, a single exposure to attenuated parasites revealed early establishment of a Th1 bias (signaling of IL-1, IFN-γ; and Leishmania infection). Genes encoding chemokines and their receptors were more prominent in vaccinated mice, indicating an enhanced capacity for inflammation, potentially augmenting the inhibition of intravascular migration. Increasing the vaccinations from one to three did not dramatically elevate protection, but there was a clear shift towards antibody-mediated effectors. However, elements of the Th1 bias were still evident. Notable features after three vaccinations were markers of cytotoxicity (including IL-6 and NK cells) together with growth factors and their receptors (FGFR/VEGF/EGF) and the apoptosis pathway. Indeed, there is evidence for the development of anergy after three vaccinations, borne out by the limited responses detected in samples after challenge. We infer that persistence of a Th1 response puts a limit on expression of antibody-mediated mechanisms. This feature may explain the failure of multiple doses to drive protection towards sterile immunity. We suggest that the secretions of lung stage parasites would make a novel cohort of antigens for testing in protection experiments.

Diversos autores chamam a atenção para a correlação entre disfunções sexuais e ansiedade. Kaplan (1983) admite que a ansiedade é o "pano de fundo" de todas as disfunções sexuais, e que quanto mais severa, mais intensamente bloqueará a resposta sexual, atingindo desse modo o desejo, como forma de impedimento maior para que qualquer outra fase se desenvolva. O Transtorno de Pânico (TP) é considerado, pela Organização Mundial de Saúde, em sua décima classificação internacional de doenças, (CID 10, (1993)), como uma das formas mais freqüentes de ansiedade. A partir destes dados procuramos relacionar o Transtorno de Pânico ao Transtorno de Desejo Sexual Hipoativo (TDSH). Participaram desta pesquisa 26 pacientes, homens e mulheres, que procuraram espontaneamente atendimento ambulatorial em psiquiatria no Hospital Municipal Lourenço Jorge e no Hospital da Santa Casa de Misericórdia, ambos situados na cidade do Rio de Janeiro. Obrigatoriamente estes pacientes satisfizeram os critérios diagnósticos do Manual Diagnóstico e Estatístico de Transtornos Mentais, Texto Revisado (DSM-IV-TR, (2002)), para "TP com ou sem Agorafobia". Os pacientes responderam a um questionário de auto-avaliação extraído e modificado de Masters, Johnson & Kolodny, (1997) que pretende avaliar a freqüência de redução do desejo sexual nesta população de pacientes. A análise estatística foi realizada através dos testes de Wilcoxon e U de Mainn-Whitney e indicam, a existência de uma associação estatisticamente significativa, entre TP com ou sem Agorafobia e TDSH(como definido pelo DSM-IV-TR, (2002).