The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases.

BACKGROUND AND PURPOSE Cognitive impairment is frequent among patients with mild traumatic brain injury despite the absence of detectable damage on conventional MR imaging. In this study, the quantitative MR imaging techniques DTI, DKI, and ASL were used to measure changes in the structure and function in the thalamus and WM of patients with MTBI during a short follow-up period, to determine whether these techniques can be used to investigate relationships with cognitive performance and to predict outcome. MATERIALS AND METHODS Twenty patients with MTBI and 16 controls underwent MR imaging at 3T and a neuropsychological battery designed to yield measures for attention, concentration, executive functioning, memory, learning, and information processing. MK, FA, MD, and CBF were measured in the thalamus by using region-of-interest analysis and in WM by using tract-based spatial statistics. Analyses were performed comparing regional imaging measures of subject groups and the results of testing of their associations with neuropsychological performance. RESULTS Patients with MTBI exhibited significant differences from controls for DTI, DKI, and ASL measures in the thalamus and various WM regions both within 1 month after injury and >9 months after injury. At baseline, DTI and DKI measures in the thalamus and various WM regions were significantly associated with performance in different neuropsychological domains, and cognitive impairment was significantly associated with MK in the thalamus and FA in optic radiations. CONCLUSIONS Combined application of DTI, DKI, and ASL to study MTBI might be useful for investigating dynamic changes in the thalamus and WM as well as cognitive impairment during a short follow-up period, though the small number of patients examined did not predict outcome.

This functional model of hepatocyte transplantation is validated for the study of host immune responses to hepatocellular grafts and to assess efficacy of strategies designed to alter these in vivo immune responses. The immunologic rejection of allogeneic hepatocytes appears to be T cell-mediated.

C-reactive protein (CRP), the prototypic acute-phase reactant in humans, is synthesized in liver in response to a wide variety of inf lammatory stimuli. We have generated a line of transgenic mice that express rabbit CRP from the rat phosphoenolpyruvate carboxykinase (PEPCK) promoter in response to gluconeogenic signals. Here we show that transgenic mice expressing high levels of CRP were partially protected from a lethal challenge of bacterial lipopolysaccharide compared with littermates in which CRP expression had been suppressed. Similar protection was observed with challenges from platelet-activating factor (PAF) and the combination of tumor necrosis factor ␣ (TNF-␣) plus interleukin 1␤, but not with TNF-␣ alone. We further demonstrate that although PAF was able to bind CRP, the mechanism by which CRP provides protection probably does not involve sequestration of PAF. The biologically inactive precursor of PAF, lyso-PAF, also bound CRP but did not render the transgenic mice sensitive to PAF when CRPexpressing animals were simultaneously challenged with PAF and an excess of lyso-PAF. These results suggest that CRP functions in vivo by modulating host defense systems.