672 research outputs found
Disorders of keratinisation: from rare to common genetic diseases of skin and other epithelial tissues
Metal-Rich M-dwarf Planet Hosts: Metallicities with K-Band Spectra
A metal-rich environment facilitates planet formation, making metal-rich
stars the most favorable targets for surveys seeking to detect new exoplanets.
Using this advantage to identify likely low-mass planet hosts, however, has
been difficult: until now, methods to determine M-dwarf metallicities required
observationally expensive data (such as parallaxes and high-resolution
spectra), and were limited to a few bright cool stars. We have obtained
moderate (R~2700) resolution K-band spectra of 17 M-dwarfs with metallicity
estimates derived from their FGK companions. Analysis of these spectra, and
inspection of theoretical synthetic spectra, reveal that an M-dwarf's
metallicity can be inferred from the strength of its Na I doublet (2.206 {\mu}m
& 2.209 {\mu}m) and Ca I triplet (2.261 {\mu}m, 2.263 {\mu}m & 2.265 {\mu}m)
absorption lines. We use these features, and a temperature-sensitive water
index, to construct an empirical metallicity indicator applicable for M-dwarfs
with near-solar metallicities (-0.5<[Fe/H]<+0.5). This indicator has an
accuracy of +/- 0.15 dex, comparable to that of existing techniques for
estimating M-dwarf metallicities, but is more observationally accessible,
requiring only a moderate resolution K-band spectrum. Applying this method to 8
known M-dwarf planet hosts, we estimate metallicities ([Fe/H]) in excess of the
mean metallicity of M-dwarfs in the solar neighborhood, consistent with the
metallicity distribution of FGK planet hosts.Comment: 16 pages, 4 figures, accepted for publication on ApJ
Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis
BackgroundAtopic dermatitis (AD; eczema) is characterized by a widespread abnormality in cutaneous barrier function and propensity to inflammation. Filaggrin is a multifunctional protein and plays a key role in skin barrier formation. Loss-of-function mutations in the gene encoding filaggrin (FLG) are a highly significant risk factor for atopic disease, but the molecular mechanisms leading to dermatitis remain unclear.ObjectiveWe sought to interrogate tissue-specific variations in the expressed genome in the skin of children with AD and to investigate underlying pathomechanisms in atopic skin.MethodsWe applied single-molecule direct RNA sequencing to analyze the whole transcriptome using minimal tissue samples. Uninvolved skin biopsy specimens from 26 pediatric patients with AD were compared with site-matched samples from 10 nonatopic teenage control subjects. Cases and control subjects were screened for FLG genotype to stratify the data set.ResultsTwo thousand four hundred thirty differentially expressed genes (false discovery rate, P < .05) were identified, of which 211 were significantly upregulated and 490 downregulated by greater than 2-fold. Gene ontology terms for “extracellular space” and “defense response” were enriched, whereas “lipid metabolic processes” were downregulated. The subset of FLG wild-type cases showed dysregulation of genes involved with lipid metabolism, whereas filaggrin haploinsufficiency affected global gene expression and was characterized by a type 1 interferon–mediated stress response.ConclusionThese analyses demonstrate the importance of extracellular space and lipid metabolism in atopic skin pathology independent of FLG genotype, whereas an aberrant defense response is seen in subjects with FLG mutations. Genotype stratification of the large data set has facilitated functional interpretation and might guide future therapy development
Changes in nano-mechanical properties of human epidermal cornified cells in children with atopic dermatitis
Background: Impaired skin barrier is an important etiological factor in atopic dermatitis (AD). The structural protein filaggrin (FLG) plays a major role in maintenance of the competent skin barrier and its deficiency is associated with enhanced susceptibility to mechanical injury. Here we examined biomechanical characteristics of the corneocytes in children with AD and healthy controls. Methods: We recruited 20 children with AD and 7 healthy children. They were genotyped for filaggrin gene ( FLG) loss-of-function mutations. Stratum corneum was collected from clinically unaffected skin by adhesive tapes. Cell stiffness (apparent elastic modulus, Ea) was determined by atomic force microscopy and filaggrin degradation products (NMF) by liquid chromatography. Skin barrier function was assessed through trans-epidermal water loss (TEWL) and disease severity by the SCORing Atopic Dermatitis (SCORAD) tool. Results: Corneocytes collected from AD patients showed a decreased elastic modulus which was strongly correlated with NMF and TEWL, but not with SCORAD. As compared with healthy controls, AD patients had reduced TEWL and NMF levels regardless of FLG mutations. NMF was strongly correlated with TEWL. Conclusion: Our findings demonstrate that AD patients have decreased corneocyte stiffness which correlates with reduced levels of filaggrin degradation products, NMF and skin barrier function. Altered mechanical properties of the corneocytes likely contribute to the loss of mechanical integrity of the SC and to reduced skin barrier function in AD
Filaggrin gene loss-of-function mutations constitute a factor in patients with multiple contact allergies
Retraction notice (The Journal of Allergy and Clinical Immunology (2015) 135(4) (930–935.e1), (S009167491401793X), (10.1016/j.jaci.2014.12.013))
Development of a Corneal Bioluminescence Mouse for Real-Time In Vivo Evaluation of Gene Therapies
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Periodic Radio Emission From the M7 Dwarf 2mass J13142039+1320011: Implications for the Magnetic Field Topology
We present multi-epoch radio and optical observations of the M7 dwarf 2MASS J13142039+1320011. We detect a ∼ 1 mJy source at 1.43, 4.86, 8.46 and 22.5 GHz, making it the most luminous radio emission over the widest frequency range detected from an ultracool dwarf to date. A 10 hr VLA observation reveals that the radio emission varies sinusoidally with a period of 3.89±0.05 hr, and an amplitude of ≈ 30% at 4.86 GHz and ≈ 20% at 8.46 GHz. The periodicity is also seen in circular polarization, where at 4.86 GHz the polarization reverses helicity from left- to right-handed in phase with the total intensity. An archival detection in the FIRST survey indicates that the radio emission has been stable for at least a decade. We also detect periodic photometric variability in several optical filters with a period of 3.79 hr, and measure a rotation velocity of vsini = 45 ± 5 km s−1, in good agreement with the radio and optical periods. The period and rotation velocity allow us to place a lower limit on the radius of the source of & 0.12 R⊙, about 30% larger than theoretical expectations. The properties of the radio emission can be explained with a simple model of a magnetic dipole mis-aligned relative to the stellar rotation axis, with the sinusoidal variations and helicity reversal due to the rotation of the magnetic poles relative to our line of sight. The long-term stability of the radio emission indicates that the magnetic field (and hence the dynamo) is stable on a much longer timescale than the convective turn-over time of ∼ 0.2 yr. If the radio emission is due to the electron cyclotron maser process, the inferred magnetic field strength reaches at least 8 kG.Astronom
Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure
Background
Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema.
Methods and Findings
We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen(n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27–4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79–32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24–1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13–3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35–10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16–2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation.
Conclusions
We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life
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