Exeter City Council

Atopic dermatitis (AD) is a common chronic skin disorder characterised by a highly inflamed local environment and elevated epidermal proteolytic activity. Changes in the skin mycobiome have been observed in this disease, specifically Candida albicans colonization positively correlating with AD severity, yet the mechanisms by which this fungus contributes to disease features remain elusive. This study aimed to elucidate how C. albicans can influence AD pathogenesis through its influence on keratinocyte (KC) proteolytic activity, inflammatory cytokine secretion and epidermal barrier integrity, as well as define the signaling pathways mediating these effects. Immortalized human KC were co-cultured with C. albicans and changes in KC protease expression and activity, along with the secretion of the pro-inflammatory cytokine IL-1β were assessed. Additionally, the impact of IL-1β on KC barrier formation was determined using transepithelial electrical resistance. To identify signalling pathways mediating Candida-induced phenotypes, CRISPR/Cas9 was used to establish cell lines deficient in myeloid differentiation primary response protein 88 (MyD88) or matrix metalloprotease-9 (MMP-9). C. albicans induced proteolytic activity from KC through fungal secreted aspartyl proteases (Sap4-6) and promoted IL-1β secretion via MyD88 signalling. This response increased expression and activation of host MMP-9 and led to impaired barrier function. Genetic deletion of either MYD88 or MMP9 restored barrier function in IL-1β treated cells, suggesting MMP-9 serves as a downstream effector of IL-1β/MyD88 signalling. These findings establish a mechanistic link between skin resident fungi and epidermal barrier dysfunction. We demonstrate a pathway linking fungal colonization to innate immune responses by skin cells, providing insight into how the commensal fungus C. albicans may contribute to AD pathogenesis.

The use of soluble fusion proteins of pattern recognition receptors (PRRs) used in the detection of exogenous and endogenous ligands has helped resolve the roles of PRRs in the innate immune response to pathogens, how they shape the adaptive immune response, and function in maintaining homeostasis. Using the immunoglobulin (Ig) crystallizable fragment (Fc) domain as a fusion partner, the PRR fusion proteins are soluble, stable, easily purified, have increased affinity due to the Fc homodimerization properties, and consequently have been used in a wide range of applications such as flow cytometry, screening of protein and glycan arrays, and immunofluorescent microscopy. This review will predominantly focus on the recognition of pathogens by the cell membrane-expressed glycan-binding proteins of the C-type lectin receptor (CLR) subgroup of PRRs. PRRs bind to conserved pathogen-associated molecular patterns (PAMPs), such as glycans, usually located within or on the outer surface of the pathogen. Significantly, many glycans structures are identical on both host and pathogen (e.g. the Lewis (Le) X glycan), allowing the use of Fc CLR fusion proteins with known endogenous and/or exogenous ligands as tools to identify pathogen structures that are able to interact with the immune system. Screens of highly purified pathogen-derived cell wall components have enabled identification of many unique PAMP structures recognized by CLRs. This review highlights studies using Fc CLR fusion proteins, with emphasis on the PAMPs found in fungi, bacteria, viruses, and parasites. The structure and unique features of the different CLR families is presented using examples from a broad range of microbes whenever possible.

Outbreaks of fungal infections due to emerging and rare species are increasingly reported in healthcare settings. We investigated a pseudo-outbreak of Rhinocladiella similis in a bronchoscopy unit of a tertiary care teaching hospital in London, UK. We aimed to determine route of healthcare-associated transmission and prevent additional infections. From July 2018 through February 2019, we detected a pseudo-outbreak of R.similis isolated from bronchoalveolar lavage (BAL) fluid samples collected from nine patients who had undergone bronchoscopy in a multispecialty teaching hospital, during a period of 8months. Isolates were identified by MALDI-TOF mass spectrometry. Antifungal susceptibility testing was performed by EUCAST broth microdilution. To determine genetic relatedness among R.similis isolates, we undertook amplified fragment length polymorphism analysis. To determine the potential source of contamination, an epidemiological investigation was carried out. We reviewed patient records retrospectively and audited steps taken during bronchoscopy as well as the subsequent cleaning and decontamination procedures. Fungal cultures were performed on samples collected from bronchoscopes and automated endoscope washer-disinfector systems. No patient was found to have an infection due to R.similis either before or after bronchoscopy. One bronchoscope was identified to be used among all affected patients with positive fungal cultures. Physical damage was found in the index bronchoscope; however, no fungus was recovered after sampling of the affected scope or the rinse water of automated endoscope washer-disinfectors. Use of the scope was halted, and, during the following 12-month period, Rhinocladiella species were not isolated from any BAL specimen. All pseudo-outbreak isolates were identified as R.similis with high genetic relatedness (>90% similarity) on ALFP analysis. The study emphasises the emergence of a rare and uncommon black yeast R.similis, with reduced susceptibility to echinocandins, in a bronchoscope-related pseudo-outbreak with a potential water-related reservoir. Our findings highlight the importance of prolonged fungal culture and species-level identification of melanised yeasts isolated from bronchoscopy samples. Possibility of healthcare-associated transmission should be considered when R.similis is involved in clinical microbiology samples.

Background: Individual differences in biological maturation impact player selection and development in youth football.Aim: To evaluate players perceptions of competing in a football tournament where they were matched by maturity rather than chronological age.Subjects: Participants included male junior footballers from three professional academies (n = 115).Methods: The study employed multiple methods of analysis, including one sample mean t-tests, equivalence tests, ANOVAs, and thematic analysis of qualitative data derived from open-ended questions.Results and conclusions: Player’s perceived the bio-banding format as providing two main benefits. Early maturing players perceived greater physical and technical challenge, and in turn new opportunities and challenges. Late maturing players perceived less physical and technical challenge, yet greater opportunity to demonstrate technical and tactical abilities. The players reported that they enjoyed and understood the purpose of the bio-banded format, and perceived less risk for injury. Players in all three maturity groups reported more opportunity to engage in leadership behaviours, influence game-play, and express themselves on the ball in the bio-banded format. Bio-banding may facilitate development for both early and late maturing academy players by presenting new learning environments and challenges.

Moulton's catalogue Get access H. Tapley-Soper H. Tapley-Soper 1City Library, Exeter Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume 190, Issue 6, 23 March 1946, Page 129, https://doi.org/10.1093/nq/190.6.129d Published: 23 March 1946

Journal Article Books bound in human skin Get access H. Tapley-Soper H. Tapley-Soper 1City Library, Exeter Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume 187, Issue 14, 30 December 1944, Page 306, https://doi.org/10.1093/nq/187.14.306d Published: 30 December 1944