Tumor necrosis factor (TNF)-␣ induces cytoskeleton and intercellular junction remodeling in tubular epithelial cells; the underlying mechanisms, however, are incompletely explored. We have previously shown that ERK-mediated stimulation of the RhoA GDP/GTP exchange factor GEF-H1/Lfc is critical for TNF-␣-induced RhoA stimulation. Here we investigated the upstream mechanisms of ERK/GEF-H1 activation. Surprisingly, TNF-␣-induced ERK and RhoA stimulation in tubular cells were prevented by epidermal growth factor receptor (EGFR) inhibition or silencing. TNF-␣ also enhanced phosphorylation of the EGFR. EGF treatment mimicked the effects of TNF-␣, as it elicited potent, ERK-dependent GEF-H1 and RhoA activation. Moreover, EGF-induced RhoA activation was prevented by GEF-H1 silencing, indicating that GEF-H1 is a key downstream effector of the EGFR. The TNF-␣-elicited EGFR, ERK, and RhoA stimulation were mediated by the TNF-␣ convertase enzyme (TACE) that can release EGFR ligands. Further, EGFR transactivation also required the tyrosine kinase Src, as Src inhibition prevented TNF-␣-induced activation of the EGFR/ERK/ GEF-H1/RhoA pathway. Importantly, a bromodeoxyuridine (BrdU) incorporation assay and electric cell substrate impedance-sensing (ECIS) measurements revealed that TNF-␣ stimulated cell growth in an EGFR-dependent manner. In contrast, TNF-␣-induced NFB activation was not prevented by EGFR or Src inhibition, suggesting that TNF-␣ exerts both EGFR-dependent and -independent effects. In summary, in the present study we show that the TNF-␣-induced activation of the ERK/GEF-H1/RhoA pathway in tubular cells is mediated through Src-and TACE-dependent EGFR activation. Such a mechanism could couple inflammatory and proliferative stimuli and, thus, may play a key role in the regulation of wound healing and fibrogenesis.
Dysfunction in cortico-limbic circuitry is implicated in internalizing disorders (i.e., depressive and anxious disorders), but less is known about whether structural variations precede frank disorder and thus potentially mark risk. We therefore examined associations between white matter (WM) tract microstructure in cortico-limbic circuitry at age 7 and concurrent and longitudinal patterns of internalizing symptoms in 42 typically developing girls using Diffusion Tensor Imaging (DTI). Girls' internalizing symptoms were concurrently associated with reduced fractional anisotropy (FA) in segments of the cingulum bundle (CB) and the uncinate fasciculus (UF), bilaterally. Moreover, latent profile analysis showed that girls with increasing internalizing symptoms, based on assessments at ages 3, 6, 7, and 8, had reduced FA in these segments compared to girls with stably low symptoms. These results point to a putative neural mechanism underlying the course of childhood internalizing symptoms.
Aim: To assess the feasibility of a randomized pilot trial that evaluated the acceptability and potential clinical utility of the Mindfulness Ambassador Program (MAP), a unique, standardized 12-session facilitated group mindfulness-based intervention (MBI) for youth experiencing early psychosis.Methods: Twenty-one patients of an early psychosis intervention program were randomized to receive MAP (n = 11) or treatment as usual (n = 10). Acceptability was measured by group attendance rate and client satisfaction; feasibility of the study design was measured by the recruitment and retention rate. The means, standard deviations, and 95% confidence intervals were described for outcomes of interest.Results: MAP is associated with a high degree of acceptability and has beneficial effects for depression and fatigue. The randomized trial design is feasible.Conclusions: This study provides important pilot data supporting a larger randomized trial of effectiveness for MAP as a group MBI for early psychosis. Details of MAP and study limitations are discussed.
K E Y W O R D Saffective symptoms, early medical intervention, mindfulness, psychosis, schizophrenia
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