Protein Expression of Fibroblast Growth Factor Receptor–1 in Keratinocytes During Wound Healing in Rat Skin

Fibroblast growth factors have been shown to play important roles in wound healing. To define their sites of action, we examined the expression of fibroblast growth factor receptor–1 (FGFR-1) during burn wound healing in rat skin by immunohistochemistry and western blot analysis. In cryostat sections of intact skin, little or no staining was observed. After a burn, however, staining for FGFR-1 was found in newly forming epidermis. The suprabasal layer of such epidermis, composed mostly of regenerating keratinocytes, was stained intensely, whereas keratinocytes in newly forming hair follicles were devoid of staining. Staining gradually decreased week by week after wound closure and was hardly visible 10 weeks after the burn, when the thickness of the epidermis had returned to the normal level. Staining was also found in small blood vessels and capillaries of granulation tissues of the dermis. Western blot analysis using the same antiserum was performed in the newly forming epidermis 10 d after the burn. A single band was detected with an apparent molecular weight of 120 kDa, corresponding to the short membrane-bound form of rat FGFR-1. Our study indicates that FGFR-1 is expressed during wound healing, mainly in regenerating epidermis and to some extent in blood vessels of the dermis. Fibroblast growth factors may affect the proliferation and differentiation of epidermal keratinocytes as well as angiogenesis in the dermis via the FGFR-1 expressed during wound healing

Histamine Induces the Generation of Monocyte-Derived Dendritic Cells that Express CD14 but not CD1a

The local cytokine environment and the presence of stimulatory signals determine whether monocytes acquire dendritic cell or macrophage characteristics and functions. In this study, we examined the effect of histamine, a prototypic mediator of allergic inflammation, on the granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4-driven differentiation of monocytes into monocyte-derived dendritic cells (MoDC), which typically showed CD1a+CD14- phenotype. Monocytes from healthy adult donors were cultured with GM-CSF and IL-4 in the presence or absence of histamine, and the phenotypes and function of these cells were analyzed. Histamine induced the generation of CD1a-CD14+ cells, which exhibited cytological and phenotypical characteristics of dendritic cells (DC), showed enhanced phagocytic activity and cytokine-producing capacity, but demonstrated weak allo-stimulatory capacity compared with CD1a+CD14- MoDC. The inhibitory effects of histamine on CD1a+CD14- MoDC differentiation were antagonized by cimetidine, an H2 receptor antagonist, but not by H1 and H3 receptor blockers, and were mimicked by an H2 receptor agonist. Culture supernatant of histamine-treated monocytes also inhibited CD1a+CD14- MoDC differentiation, which was restored by the removal of IL-10. These results suggest that histamine-driven CD1a-CD14+ DC amplify their antigen-independent inflammatory reaction and may contribute to the exacerbation of allergic diseases

Elevated Platelet Activation in Patients with Atopic Dermatitis and Psoriasis: Increased Plasma Levels of β-Thromboglobulin and Platelet Factor 4

Background: Beyond their role in hemostasis and thrombosis, platelets are important for modulating inflammatory reactions. Activated platelets play a role in the pathomechanism of inflammatory diseases such as asthma, but little is known about platelet activation in chronic skin inflammation, including atopic dermatitis (AD) and psoriasis. Furthermore, the relationship between platelet activation and disease severity is not understood. This work was performed to investigate plasma levels of β-thromboglobulin (β-TG) and platelet factor 4 (PF4) as platelet activation markers in patients with AD or psoriasis, and to determine the relationships between these markers and disease severity. Methods: Plasma levels of β-TG and PF4 were measured by enzyme-linked immunoassay in 22 healthy controls, 44 patients with AD, and 16 patients with psoriasis. The relationships between these markers and the scoring AD (SCORAD) index, blood eosinophilia, serum IgE and serum lactate dehydrogenase were investigated in AD patients, and relationships with the psoriasis area and severity index (PASI) score were examined in psoriatic patients. Results: Plasma β-TG and PF4 levels were significantly higher in patients with AD or psoriasis compared with healthy controls. β-TG and PF4 levels correlated with the SCORAD index, and PF4 levels correlated with PASI scores. Elevated β-TG and PF4 levels were significantly reduced after treatments. Conclusions: Our results show that blood platelets are activated in patients with AD or psoriasis, suggesting that activated platelets play a role in the pathomechanism of chronic skin inflammation. Furthermore, plasma β-TG and PF4 may be markers for the severity of AD and psoriasis

Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process

The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a fitness-increasing evolutionary process. The dynamics of genome mutation fixation in the thermal adaptive evolution of Escherichia coli were evaluated in a prolonged evolution experiment in duplicated lineages. The cells from the continuously fitness-increasing evolutionary process were subjected to genome sequencing and analyzed at both the population and single-colony levels. Although the dynamics of genome mutation fixation were complicated by the combination of the stochastic appearance of adaptive mutations and clonal interference, the mutation fixation in the population was simply linear over generations. Each genome in the population accumulated 1.6 synonymous and 3.1 non-synonymous neutral mutations, on average, by the spontaneous mutation accumulation rate, while only a single genome in the population occasionally acquired an adaptive mutation. The neutral mutations that preexisted on the single genome hitchhiked on the domination of the adaptive mutation. The successive fixation processes of the 128 mutations demonstrated that hitchhiking and not genetic drift were responsible for the coincidence of the spontaneous mutation accumulation rate in the genome with the fixation rate of neutral mutations in the population. The molecular clock of neutral mutations to the fitness-increasing evolution suggests that the numerous neutral mutations observed in molecular phylogenetic trees may not always have been fixed in fitness-steady evolution but in adaptive evolution

Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process

<div><p>The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a fitness-increasing evolutionary process. The dynamics of genome mutation fixation in the thermal adaptive evolution of <i>Escherichia coli</i> were evaluated in a prolonged evolution experiment in duplicated lineages. The cells from the continuously fitness-increasing evolutionary process were subjected to genome sequencing and analyzed at both the population and single-colony levels. Although the dynamics of genome mutation fixation were complicated by the combination of the stochastic appearance of adaptive mutations and clonal interference, the mutation fixation in the population was simply linear over generations. Each genome in the population accumulated 1.6 synonymous and 3.1 non-synonymous neutral mutations, on average, by the spontaneous mutation accumulation rate, while only a single genome in the population occasionally acquired an adaptive mutation. The neutral mutations that preexisted on the single genome hitchhiked on the domination of the adaptive mutation. The successive fixation processes of the 128 mutations demonstrated that hitchhiking and not genetic drift were responsible for the coincidence of the spontaneous mutation accumulation rate in the genome with the fixation rate of neutral mutations in the population. The molecular clock of neutral mutations to the fitness-increasing evolution suggests that the numerous neutral mutations observed in molecular phylogenetic trees may not always have been fixed in fitness-steady evolution but in adaptive evolution.</p></div