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Inspired by the Renaissance artist and polymath Leonardo da Vinci as an ADHD (attention deficit hyperactivity disorder) archetype celebrated for his creativity, brilliance, endless curiosity, and experimentation, this article brings to awareness links between genetic traits and neurodivergence. It seeks to rethink the ADHD diagnosis and proposes a TA-neurodiversity affirming lens for navigating neuronormativity as well as healing from its oppressive structural and systemic processes. In particular, impasses are explored in the context of how neuronormativity impacts relational material and drives adaptive masking patterns, racketeering, and script formation. The authors present the masking-authenticity triangle framework, which provides an intersectional and standpoint epistemological inquiry into the clinical presentation and developmental trajectory of neurodivergent masking. [ABSTRACT FROM AUTHOR]

Background: Dermatophytosis is one of the most common infections affecting 3%–17% of the population. Resistance to antifungals so far was not of concern in the therapeutic management. However, recent reports of terbinafine‐resistant strains in several countries are worrisome making antifungal susceptibility testing inevitable. Objectives: We aimed to develop and evaluate an optimised broth microdilution assay for antifungal drug susceptibility testing of dermatophytes. Methods: We first studied the effect of different inocula, incubation temperatures and incubation times to establish an optimised assay. Subsequently, we tested 79 clinical strains of 11 dermatophyte species with 13 antifungals. Results: We found inoculating with 0.5–5 × 104 colony forming units (CFU) and incubating at 29°C ± 1°C for 4 days to be appropriate. Terbinafine was the most active antifungal agent with minimum inhibitory concentration (MIC) values ≤ 0.06 µg/mL, expect for one resistant T mentagrophytes strain, which was isolated from an Indian patient. Also, a majority of MICs of other antifungals that are commonly used to treat dermatophytosis were low, except those of fluconazole. Fluconazole MICs do not correlate with the good efficacy in the clinical management. Conclusions: Our assay enables fast and reliable susceptibility testing of dermatophytes with a large panel of different antifungals. This helps to improve the therapeutic management of dermatophytosis by detecting resistant strains. [ABSTRACT FROM AUTHOR]

Malassezia restricta and Malassezia globosa are lipid dependent commensal yeasts associated with dandruff. Antifungal actives such as zinc pyrithione are commonly used in antidandruff shampoos, although their efficacy is not clearly demonstrated. In this study, we assessed the efficacy of antifungal treatments on scalp Malassezia via a combination of culturomic and genomic detection methods. Zinc pyrithione inhibited Malassezia growth at low minimum inhibitory concentrations (MICs). In a longitudinal pilot study, quantitative polymerase chain reaction (qPCR) analysis showed a decrease in M. restricta on the scalp after zinc pyrithione treatment. These findings validate the antifungal efficacy of zinc pyrithione as a dandruff treatment. Lay Abstract Malassezia yeasts are associated with dandruff and seborrheic dermatitis. Zinc pyrithione is effective against Malassezia growth in vitro and when tested on human skin as a shampoo. These findings will be useful for investigating the role of Malassezia in skin microbiome intervention studies. [ABSTRACT FROM AUTHOR]

Commensal fungi such as Malassezia , Candida , and Rhodotorula are common on healthy skin but are also associated with opportunistic invasive and superficial infections. Skin microbial community characterization has been extensively performed worldwide, with a focus on the 16S bacterial community. These studies have focused on geographically distinct or targeted cohorts with variable reported species distributions of commensal yeast species. To determine the effects of extrinsic environmental factors such as geography, climate, and ethnicity on detected healthy skin commensal yeast diversity, we compared cohorts from Singapore and Zürich, Switzerland, representative of two geographically and climatically distinct regions comprising multi-ethnic (Chinese, Malay, Indian, Caucasian) and predominantly white Caucasian cohorts, respectively, using identical skin sampling and culture methods. We chose to use a culture-based approach as cultures isolated from patients are still required for studies of pathogenicity and antifungal susceptibility. Detection of yeast species by culture-dependent and independent sequencing-based methods suggest healthy skin diversity reflects a species distribution representative of the geography, climate and ethnic background of their local populations. Culture success and species diversity was also found to be dependent on climate, with warm tropical climates favoring high positive culture rates and greater species diversity. Multilocus sequence typing data suggests some strains are geographically distinct and may be used to segregate potential disease-causing commensals. For accurate collection and characterization of skin microbial communities, it remains recommended to employ a combination of culture-dependent and sequence-based culture-independent methods. Characterization of healthy mycobiomes in geographically distinct local populations will be useful in defining the role of commensal fungi in health and disease. [ABSTRACT FROM AUTHOR]

Abstract: Phototherapy is routinely used for the treatment of various skin conditions and targeted therapy of superficial cancers. However, the molecular mechanisms behind their biological effects and the need for efficacy enhancing photosensitizers are not well addressed. Particularly, not much is known about the inherent effect of light from the visible spectrum on cytokine release and its downstream effects in keratinocytes and immune cells located in skin and therefore exposed to light. To address this, we delivered calibrated doses of well‐defined light qualities (380 to 660 nm) to cocultures of human keratinocytes and macrophage/dendritic cells in the absence or presence of the commonly used photosensitizer 8‐methoxypsoralen (8‐MOP). The experiments identified IL‐4 as a key effector cytokine released by this coculture model with need for 8‐MOP in the UVA1/blue (380 nm) and no requirement for photosensitizer in the red light spectrum (627 nm). 3D organotypic skin cultures treated with IL‐4 showed thickening of the epidermal layer and delayed differentiation. However unlike IL‐4 and UVA1/blue light treatment, red light did not reduce the expression of keratinocyte differentiation markers or increase signs of photo‐oxidative damage. This supports the application of isolated red light as a possible alternative for photo‐immunotherapy without need for additional photosensitizers. [ABSTRACT FROM AUTHOR]

Opioids in skin function during stress response, regeneration, ageing and, particularly in regulating sensation. In chronic pruritus, topical treatment with Naltrexone changes μ-opioid receptor (μ-OR) localization to relieve itch. The molecular mechanisms behind the effects of Naltrexone on μ-OR function in reduction of itching behavior has not been studied. There is an immediate need to understand the endogenous complexity of μ-OR dynamics in normal and pathological skin conditions. Here we evaluate real-time behavior of μ-OR-Endomorphine complexes in the presence of agonist and antagonists. The μ-OR ligand Endomorphine-1 (EM) was conjugated to the fluorescent dye Tetramethylrhodamine (TAMRA) to investigate the effects of agonist and antagonists in N/TERT-1 keratinocytes. The cellular localization of the EM-TAMRA was followed through time resolved confocal microscopy and population analysis was performed by flow cytometry. The in vitro analyses demonstrate fast internalization and trafficking of the endogenous EM-TAMRA-μ-OR interactions in a qualitative manner. Competition with Endomorphine-1, Naltrexone and CTOP show both canonical and non-canonical effects in basal and differentiated keratinocytes. Acute and chronic treatment with Naltrexone and Endomorphine-1 increases EM-TAMRA binding to skin cells. Although Naltrexone is clinically effective in relieving itch, the mechanisms behind re-distribution of μ-ORs during clinical treatments are not known. Our study has given insight into cellular mechanisms of μ-OR ligand-receptor interactions after opioid agonist and antagonist treatments in vitro. These findings potentially offer opportunities in using novel treatment strategies for skin and peripheral sensory disorders. [ABSTRACT FROM AUTHOR]

To address existing limitations in live neuron imaging, we have developed NeuO, a novel cell-permeable fluorescent probe with an unprecedented ability to label and image live neurons selectively over other cells in the brain. NeuO enables robust live neuron imaging and isolation in vivo and in vitro across species; its versatility and ease of use sets the basis for its development in a myriad of neuronal targeting applications. [ABSTRACT FROM AUTHOR]

Investigation of the genetic functions in complex biological systems is a challenging step in recent year. Hence, several valuable and interesting research projects have been developed with novel ideas to find out the unknown functions of genes or proteins. To validate the applicability of their novel ideas, various approaches are built up. To date, the most promising and commonly used approach for discovering the target proteins from biological system using small molecule is well known a forward chemical genetics which is considered to be more convenient than the classical genetics. Although, the forward chemical genetics consists of the three basic components, the target identification is the most challenging step to chemical biology researchers. Hence, the diverse target identification methods have been developed and adopted to disclose the small molecule bound protein. Herein, in this review, we briefly described the first two parts chemical toolbox and screening, and then the target identifications in forward chemical genetics are thoroughly described along with the illustrative real example case study. In the tabular form, the different biological active small molecules which are the successful examples of target identifications are accounted in this research review. [ABSTRACT FROM AUTHOR]

Small molecule fluorescent probes offer significant advantages over conventional antibody and fluorescent protein labeling techniques. Here we present CDr10a and CDr10b, dyes that label live microglia specifically. They may be applied to the isolation and imaging of live microglia when investigating their role in neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

Skin microbiome sampling is currently performed with tools such as swabs and tape strips to collect microbes from the skin surface. However, these conventional approaches may be unable to detect microbes deeper in the epidermis or in epidermal invaginations. We describe a sampling tool with a depth component, a transepidermal microprojection array (MPA), which captures microbial biomass from both the epidermal surface and deeper skin layers. We leveraged the rapid customizability of 3D printing to enable systematic optimization of MPA for human skin sampling. Evaluation of sampling efficacy on human scalp revealed the optimized MPA was comparable in sensitivity to swab and superior to tape strip, especially for nonstandard skin surfaces. We observed differences in species diversity, with the MPA detecting clinically relevant fungi more often than other approaches. This work delivers a tool in the complex field of skin microbiome sampling to potentially address gaps in our understanding of its role in health and disease.

Malassezia are emerging fungal pathogens causing opportunistic skin and severe systemic infection. Nosocomial outbreaks are associated with azole resistance and understanding of the underlying mechanisms are limited to knowledge from other fungal species. Herein, we identified distinct antifungal susceptibility patterns in 26 Malassezia furfur isolates derived from healthy and diseased individuals. A Y67F CYP51 mutation was identified in five isolates of M. furfur However, this mutation alone was insufficient to induce reduce azole susceptibility in the wild type strain. RNA-seq and differential gene analysis of healthy and disease derived strains exposed to clotrimazole in vitro identified several key metabolic pathways and transporter proteins which are involved in reduce azole susceptibility. The pleiotropic drug transporter PDR10 was the single most highly upregulated transporter gene in multiple strains of M. furfur after azole treatment and increased expression of PDR10 is associated with reduced azole susceptibility in some systemic disease isolates of M. furfur Deletion of PDR10 in a pathogenic M. furfur strain with reduced susceptibility reduced MIC values to the level of that in susceptible isolates. The current dearth of antifungal technologies, globally emerging multi-azole resistance, and broad agriculture and consumer care use of azoles means improved understanding of the mechanisms underlying intrinsic and acquired azole resistance in Malassezia is crucial for development of antibiotic stewardship and antifungal treatment strategies., (Copyright © 2021 Leong et al.)

Malassezia is a genus of lipid-dependent yeasts. It is associated with common skin diseases such as pityriasis versicolor and atopic dermatitis and can cause systemic infections in immunocompromised individuals. Owing to the slow growth and lipid requirements of these fastidious yeasts, convenient and reliable antifungal drug susceptibility testing assays for Malassezia spp. are not widely available. Therefore, we optimized a broth microdilution assay for the testing of Malassezia that is based on the CLSI and EUCAST assays for Candida and other yeasts. The addition of ingredients such as lipids and esculin provided a broth medium formulation that enabled the growth of all Malassezia spp. and could be read, with the colorimetric indicator resazurin, by visual and fluorescence readings. We tested the susceptibility of 52 strains of 13 Malassezia species to 11 commonly used antifungals. MIC values determined by visual readings were in good agreement with MIC values determined by fluorescence readings. The lowest MICs were found for the azoles itraconazole, posaconazole, and voriconazole, with MIC 90 values of 0.03 to 1.0 μg/ml, 0.06 to 0.5 μg/ml, and 0.03 to 2.0 μg/ml, respectively. All Malassezia spp. were resistant to echinocandins and griseofulvin. Some Malassezia spp. also showed high MIC values for ketoconazole, which is the most widely recommended topical antifungal to treat Malassezia skin infections. In summary, our assay enables the fast and reliable susceptibility testing of Malassezia spp. with a large panel of different antifungals., (Copyright © 2017 American Society for Microbiology.)

We report here a novel fluorescent chemical probe which stains distinct neural stem/progenitor cells (NSPCs) by binding to acid ceramidase in mouse neurospheres. is distributed evenly or unevenly to the daughter cells during multiple mitoses enabling the live imaging of symmetric and asymmetric divisions of isolated NSPCs.