Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation

Atopic dermatitis is a chronic inflammatory skin disease characterized by infiltration of eosinophils, T helper cells, and mast cells. The role of mast cells in atopic dermatitis is not completely understood. To define the effects of mast cells on skin biology, we observed that mast cells regulate the homeostatic expression of epidermal differentiation complex and other skin genes. Decreased epidermal differentiation complex gene expression in mice that genetically lack mast cells (Kit(W-sh/W-sh) mice) is associated with increased uptake of protein antigens painted on the skin by dendritic cells (DCs) compared with similarly treated wild-type mice, suggesting a protective role for mast cells in exposure to nominal environmental allergens. To test this further, we crossed Kit(W-sh/W-sh) mice with signal transducer and activator of transcription 6 (i.e., Stat6) VT transgenic mice that develop spontaneous atopic dermatitis-like disease that is dependent on T helper cell 2 cytokines and is associated with high serum concentrations of IgE. We observed that Stat6VT × Kit(W-sh/W-sh) mice developed more frequent and more severe allergic skin inflammation than Stat6VT transgenic mice that had mast cells. Together, these studies suggest that mast cells regulate epidermal barrier function and have a potential protective role in the development of atopic dermatitis-like diseas

Choline esterase in cobra venom

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Increased Th2 activity and diminished skin barrier function cooperate in allergic skin inflammation

Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T-cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt−/−) develop severe atopic dermatitis lesions by 3-5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6-7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt−/− mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD

Update On The Zebrafish Genome Project

The zebrafish genome, which consists of 25 linkage groups and is ~1.4Gb in size, is being sequenced, finished and analysed in its entirety at the Wellcome Trust Sanger Institute. The manual annotation is provided by the Human and Vertebrate Analysis and Annotation (HAVANA) group and is released at regular intervals onto the Vertebrate Genome Annotation (Vega) database ("http://vega.sanger.ac.uk":http://vega.sanger.ac.uk) and may be viewed as a DAS source in Ensembl ("http://www.ensembl.org/Danio_rerio":http://www.ensembl.org/Danio_rerio). 

Our annotation is compiled in close collaboration with the Zebrafish Information Network (ZFIN) ("http://zfin.org/":http://zfin.org/), which has enabled us to provide an accurate, dynamic and distinct resource for the zebrafish community as a whole.

Annotation is based on the reference genome sequence, which is derived from a minimal tile path assembly composed of clones that have been mapped, sequenced and meticulously finished to a sequence accuracy of over 99.9% per 100Kb. We expect to have 90% of the zebrafish genome to a finished standard by the end of 2009. Our approach to annotation uses two strategies. Firstly, the generation and annotation of gene lists comprising of cDNA (8995 in total) found in ZFIN that maps to our current reference assembly. And, secondly, by using clone by clone annotation, where we have annotated over 3200 genes, 1100 transcripts and 130 pseudogenes across 11 linkage groups and 3530 clones. As well as our on-going genome annotation we also welcome external annotation requests for specific genes and regions, which already include the annotation of 93 genes associated with human obesity and the scheduled annotation of the Major Histocompatability Complex, which will utilise reference sequence taken from libraries of a double haploid fish and complement our previous work on the human and mouse MHC already published.
 
External requests and any feedback, questions or requests can be sent to zfish-help [at] sanger.ac.uk

The UniProt-GO Annotation database in 2011

The GO annotation dataset provided by the UniProt Consortium (GOA: http://www.ebi.ac.uk/GOA) is a comprehensive set of evidenced-based associations between terms from the Gene Ontology resource and UniProtKB proteins. Currently supplying over 100 million annotations to 11 million proteins in more than 360 000 taxa, this resource has increased 2-fold over the last 2 years and has benefited from a wealth of checks to improve annotation correctness and consistency as well as now supplying a greater information content enabled by GO Consortium annotation format developments. Detailed, manual GO annotations obtained from the curation of peer-reviewed papers are directly contributed by all UniProt curators and supplemented with manual and electronic annotations from 36 model organism and domain-focused scientific resources. The inclusion of high-quality, automatic annotation predictions ensures the UniProt GO annotation dataset supplies functional information to a wide range of proteins, including those from poorly characterized, non-model organism species. UniProt GO annotations are freely available in a range of formats accessible by both file downloads and web-based views. In addition, the introduction of a new, normalized file format in 2010 has made for easier handling of the complete UniProt-GOA data set

A Novel System of Polymorphic and Diverse NK Cell Receptors in Primates

There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in “higher” primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire

A high utility integrated map of the pig genome

International audienc

Persistent activation of interlinked type 2 airway epithelial gene networks in sputum-derived cells from aeroallergen-sensitized symptomatic asthmatics

© 2018 The Author(s). Atopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced type 2-associated inflammation. However, the vast majority of atopics do not develop asthma despite ongoing aeroallergen exposure, suggesting additional mechanisms operate in conjunction with type 2 immunity to drive asthma pathogenesis. We employed RNA-Seq profiling of sputum-derived cells to identify gene networks operative at baseline in house dust mite-sensitized (HDM S ) subjects with/without wheezing history that are characteristic of the ongoing asthmatic state. The expression of type 2 effectors (IL-5, IL-13) was equivalent in both cohorts of subjects. However, in HDM S -wheezers they were associated with upregulation of two coexpression modules comprising multiple type 2- and epithelial-associated genes. The first module was interlinked by the hubs EGFR, ERBB2, CDH1 and IL-13. The second module was associated with CDHR3 and mucociliary clearance genes. Our findings provide new insight into the molecular mechanisms operative at baseline in the airway mucosa in atopic asthmatics undergoing natural aeroallergen exposure, and suggest that susceptibility to asthma amongst these subjects involves complex interactions between type 2- and epithelial-associated gene networks, which are not operative in equivalently sensitized/exposed atopic non-asthmatics

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Greater fuel efficiency is potentially preferable to reducing NOx emissions for aviation’s climate impacts

Aviation emissions of nitrogen oxides (NOx) alter the composition of the atmosphere, perturbing the greenhouse gases ozone and methane, resulting in positive and negative radiative forcing effects, respectively. In 1981, the International Civil Aviation Organization adopted a first certification standard for the regulation of aircraft engine NOx emissions with subsequent increases in stringency in 1992, 1998, 2004 and 2010 to offset the growth of the environmental impact of air transport, the main motivation being to improve local air quality with the assumed co-benefit of reducing NOx emissions at altitude and therefore their climate impacts. Increased stringency is an ongoing topic of discussion and more stringent standards are usually associated with their beneficial environmental impact. Here we show that this is not necessarily the right direction with respect to reducing the climate impacts of aviation (as opposed to local air quality impacts) because of the tradeoff effects between reducing NOx emissions and increased fuel usage, along with a revised understanding of the radiative forcing effects of methane. Moreover, the predicted lower surface air pollution levels in the future will be beneficial for reducing the climate impact of aviation NOx emissions. Thus, further efforts leading to greater fuel efficiency, and therefore lower CO2 emissions, may be preferable to reducing NOx emissions in terms of aviation’s climate impacts