ABSTRACT
BACKGROUND & AIMS: A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a cell surface sheddase that regulates physiologic processes, including Notch signaling. ADAM10 is expressed in all intestinal epithelial cell types, but the requirement for ADAM10 signaling in crypt homeostasis is not well defined. METHODS: We analyzed intestinal tissues from mice with constitutive (Vil-Cre;Adam10(f/f) mice) and conditional (Vil-CreER;Adam10(f/f) and Leucine-rich repeat-containing GPCR5 [Lgr5]-CreER;Adam10(f/f) mice) deletion of ADAM10. We performed cell lineage-tracing experiments in mice that expressed a gain-of-function allele of Notch in the intestine (Rosa26(NICD)), or mice with intestine-specific disruption of Notch (Rosa26(DN-MAML)), to examine the effects of ADAM10 deletion on cell fate specification and intestinal stem cell maintenance. RESULTS: Loss of ADAM10 from developing and adult intestine caused lethality associated with altered intestinal morphology, reduced progenitor cell proliferation, and increased secretory cell differentiation. ADAM10 deletion led to the replacement of intestinal cell progenitors with 2 distinct, post-mitotic, secretory cell lineages: intermediate-like (Paneth/goblet) and enteroendocrine cells. Based on analysis of Rosa26(NICD) and Rosa26(DN-MAML) mice, we determined that ADAM10 controls these cell fate decisions by regulating Notch signaling. Cell lineage-tracing experiments showed that ADAM10 is required for survival of Lgr5(+) crypt-based columnar cells. Our findings indicate that Notch-activated stem cells have a competitive advantage for occupation of the stem cell niche. CONCLUSIONS: ADAM10 acts in a cell autonomous manner within the intestinal crypt compartment to regulate Notch signaling. This process is required for progenitor cell lineage specification and crypt-based columnar cell maintenance.
Subject(s)
ADAM Proteins/metabolism , Amyloid Precursor Protein Secretases/metabolism , Intestines/enzymology , Membrane Proteins/metabolism , Receptors, Notch/metabolism , Stem Cell Niche , Stem Cells/enzymology , ADAM Proteins/deficiency , ADAM Proteins/genetics , ADAM10 Protein , Amyloid Precursor Protein Secretases/deficiency , Amyloid Precursor Protein Secretases/genetics , Animals , Cell Differentiation , Cell Line , Cell Lineage , Cell Proliferation , Cell Survival , Enteroendocrine Cells/enzymology , Goblet Cells/enzymology , Intestines/cytology , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Knockout , Organoids , Paneth Cells/enzymology , Phenotype , Signal Transduction , Time FactorsABSTRACT
Because of the need for spectrally efficient systems for wireless communication, many research activities have been carried out in the area of spread-spectrum techniques. Multi-carrier spread-spectrum (MC-SS) is a new modulation technique with better spectral properties than direct-sequence spread-spectrum (DS-SS). In this paper, a new MC-SS system is introduced. A customized surface acoustic wave (SAW) filter has been designed as a fast analog correlator. A demonstrator testbed has been developed for the 2.4-GHz industrial, scientific, and medical (ISM) band. Experimental measurements of the intermediate frequency (IF) and baseband correlation are presented.
ABSTRACT
Herewith a formula for the computation of the relative stroke volume in limbs is derived, taking into account the differences between the electrical resistivity of blood and tissues, respectively. In order to properly estimate the influence of this difference in resistivity, the appropriate variables were measured in 20 different persons. Results from these tests indicated that the value for tissue resistivity, on the average, was about 30% above that of the resistivity of blood. Consequently, computations of the stroke volume in limbs that neglect this essential difference in resistivity, contain a systematical error in measurement, amounting to 30%. It is the purpose of this paper to portray a method of considerably reducing this error, without the necessity--in each specific case--to measure blood resistivity.
