Secreted proteins in the Wnt family regulate gene expression in target cells by causing the accumulation of the transcriptional activator beta-catenin. In the absence of Wnt, a protein complex assembled around the scaffold protein Axin targets beta-catenin for destruction, thereby preventing it from transducing inappropriate signals. Loss of Axin or its binding partners APC and GSK3 results in aberrant activation of the Wnt signaling response. We have analyzed the effects of mutant forms of Drosophila Axin with large internal deletions when expressed at physiological levels in vivo, either in the presence or absence of wild type Axin. Surprisingly, even deletions that completely remove the binding sites for fly APC, GSK3 or beta-catenin, though they fail to rescue to viability, these mutant forms of Axin cause only mild developmental defects, indicating largely retained Axin function. Furthermore, two lethal Axin deletion constructs, AxinDeltaRGS and AxinDeltabeta cat(DeltaArm), can complement each other and restore viability. Our findings support a model in which the Axin complex is assembled through cooperative tripartite interactions among the binding partners, making the assembly of functional complexes surprisingly robust.

Members of the Wg/Wnt family provide key intercellular signals during embryonic development and in the maintenance of homeostatic processes, but critical aspects of their signal transduction pathways remain controversial. We have found that canonical Wg signaling in Drosophila involves distinct initiation and amplification steps, both of which require Arrow/LRP. Expressing a chimeric Frizzled2-Arrow protein in flies that lack endogenous Wg or Arrow showed that this construct functions as an activated Wg receptor but is deficient in signal amplification. In contrast, a chimeric Arrow protein containing the dimerization domain of Torso acted as a potent amplifier of Wg signaling but could not initiate Wg signaling on its own. The two chimeric proteins synergized, so that their co-expression largely reconstituted the signaling levels achieved by expressing Wg itself. The amplification function of Arrow/LRP appears to be particularly important for long-range signaling, and may reflect a general mechanism for potentiating signals in the shallow part of a morphogen gradient.

Background The rise in atopic dermatitis prevalence seen in industrialized countries in unexplained. Some authors have suggested that the increase in the use of skin care products is partly responsible. There are few studies examining skin care practices commonly used in treatment of children. We hypothesized that the use of moisturizers early in life may alter the risk for developing atopic dermatitis. Methods A case-control study utilizing two control groups was performed. Cases were defined as children under six years of age who developed atopic dermatitis. A normal control and a high-risk control group were used for comparison. Parents or caregivers of children were questioned regarding skin care practices used in early life in an attempt to identify practices that increased the risk of developing atopic dermatitis. Results The regular use of a moisturizer on the child during the first six months of life was very common in all groups, 76%, 74.7%, and 78% in the atopic, non-atopic, and high-risk groups, respectively. Because of the high rate of moisturizer use in all groups, no significant differences were found between groups. Watery lotions were the most commonly used moisturizer. Conclusions Despite published guidelines advising to the contrary, the regular use of moisturizers was common in this population. Although no one specific skin care practice was associated with atopic dermatitis, the frequent use of products potentially detrimental to the skin barrier raises concern.

Background Atopic dermatitis (AD) is a common inflammatory skin disease with global prevalence ranging from 3% to 20%. AD patients have an increased risk for complications following viral infection (e.g., herpes simplex virus), and vaccination of AD patients with live vaccinia virus is contraindicated due to a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination. Objective To develop a better understanding of immunity to cutaneous viral infection in AD patients. Methods In a double-blind, randomized study, we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of non-atopic (NA) subjects and AD patients following standard subcutaneous (SC) inoculation or transcutaneous (TC) vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T cell responses were analyzed for up to 30 days post-vaccination. Results YFV vaccination by either route was well tolerated. SC vaccination resulted in higher seroconversion rates than TC vaccination but elicited similar antiviral antibody levels and T cell responses in both NA and AD groups. Following TC vaccination, both groups mounted similar neutralizing antibody responses, but AD patients demonstrated lower antiviral T cell responses by 30 days after vaccination. Among TC-vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4+ T cell responses was observed. Conclusions YFV vaccination of AD patients by the TC route revealed that high baseline IgE levels provides a potential biomarker for predicting reduced virus-specific immune memory following TC infection with a live virus.

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