Genomic organization and cytokine-mediated inducibility of the human TRIM-8/Gerp gene.

Cytokine signaling is negatively regulated by a set of SH2 domain-containing proteins, the Suppressors of Cytokine Signaling (SOCS) acting as intracellular modulators. Experimental evidence indicates that SOCS gene expression is induced by cytokines and pro-inflammatory stimuli and is highly controlled both at transcription and translation level. Furthermore, SOCS proteins appear rapidly degraded inside the cells, mostly controlling their stability by interacting with specific molecules such as elongin B and C. It has been shown that SOCS-1/JAB, a member of the SOCS family, interacts with TRIM-8/Gerp, a new ring protein specifically binding SOCS-1 recombinant polypeptide in-vitro and in-vivo. Trim-8/Gerp, transcribes a 3.0-kb mRNA, spans 551 AA and is highly conserved during evolution. In addition, it can be induced by IFN-γ in epithelial and lymphoid cells and is expressed mostly ubiquitously in murine and human tissues. Here in this report we present the genomic organization of this new SOCS-1 interactor, and we add new tools for extending investigation of the complex mechanism that undergoes negatively regulation of cytokine signaling

Cross-Talk between Signaling Pathways Can Generate Robust Oscillations in Calcium and cAMP

BACKGROUND:To control and manipulate cellular signaling, we need to understand cellular strategies for information transfer, integration, and decision-making. A key feature of signal transduction is the generation of only a few intracellular messengers by many extracellular stimuli. METHODOLOGY/PRINCIPAL FINDINGS:Here we model molecular cross-talk between two classic second messengers, cyclic AMP (cAMP) and calcium, and show that the dynamical complexity of the response of both messengers increases substantially through their interaction. In our model of a non-excitable cell, both cAMP and calcium concentrations can oscillate. If mutually inhibitory, cross-talk between the two second messengers can increase the range of agonist concentrations for which oscillations occur. If mutually activating, cross-talk decreases the oscillation range, but can generate 'bursting' oscillations of calcium and may enable better filtering of noise. CONCLUSION:We postulate that this increased dynamical complexity allows the cell to encode more information, particularly if both second messengers encode signals. In their native environments, it is unlikely that cells are exposed to one stimulus at a time, and cross-talk may help generate sufficiently complex responses to allow the cell to discriminate between different combinations and concentrations of extracellular agonists

Hypertension and migraine comorbidity: prevalence and risk of cerebrovascular events: evidence from a large, multicenter, cross-sectional survey in Italy (MIRACLES study)

OBJECTIVES: To estimate the prevalence of hypertension-migraine comorbidity; to determine their demographic and clinical characteristics versus patients with hypertension or migraine alone; and to see whether a history of cerebrovascular events was more common in the comorbidity group. METHODS: The MIRACLES, multicenter, cross-sectional, survey included 2973 patients with a known diagnosis of hypertension or migraine in a general practitioner setting in Italy. RESULTS: Five hundred and seventeen patients (17%) suffered from hypertension-migraine comorbidity, whereas 1271 (43%) suffered from hypertension only, and 1185 (40%) from migraine only. In the comorbidity group, the onset of comorbidity occurred at about 45 years of age, with migraine starting significantly later than in the migraine-only group, and hypertension significantly before than in the hypertension-only group; a familial history of both hypertension and migraine had a significantly higher frequency as compared with the hypertension and migraine group. Compared to hypertension (3.1%) and migraine (0.7%), the comorbidity group had a higher prevalence (4.4%) of history of cerebrovascular events, with an odds ratio of a predicted history of stroke/transient ischemic attack (TIA) of 1.76 [95% confidence interval (CI) 1.01-3.07] compared to the hypertension group. In patients without other recognized risk factors for stroke, stroke/TIA occurred more frequently in the comorbidity group, compared to the hypertension group. In the age range 40-49 years, prevalence of history of stroke/TIA was five-fold greater (4.8% in comorbidity vs. 0.9% in hypertension group). CONCLUSION: This cross-sectional study indicates that the prevalence of comorbidity hypertension-migraine is substantial and that patients with comorbidity have a higher probability of history of cerebrovascular events, compared to hypertensive patient