Although the basic principles underlying the function of the peripheral auditory system have been known for many years, the molecules required for hearing have hitherto remained elusive. Genetic ...approaches have recently provided unparalleled molecular insight into how the hair bundle, the hair cell's mechanosensory organelle, forms and functions. We discuss how the proteins encoded by the Usher syndrome type 1 genes form molecular complexes required for hair-bundle development and for gating the mechanotransducer channel. We show how mouse models for nonsyndromic forms of deafness involving genes encoding Triobp and stereocilin reveal, respectively, the way stereocilia rootlets contribute to the hair bundle's mechanical properties and how the hair bundle produces suppressive masking, a property that contributes to speech intelligibility. Finally, we examine how mutations in the genes encoding α- and β-tectorin reveal multiple roles for the tectorial membrane, an extracellular matrix unique to the cochlea, in stimulating hair bundles.
Fungi are ubiquitous organisms that thrive in diverse natural environments including soils, plants, animals, and the human body. In response to warmth, humidity, and moisture, certain fungi which ...grow on crops and harvested foodstuffs can produce mycotoxins; secondary metabolites which when ingested have a deleterious impact on health. Ongoing research indicates that some mycotoxins and, more recently, peptide toxins are also produced during active fungal infection in humans and experimental models. A combination of innate and adaptive immune recognition allows the host to eliminate invading pathogens from the body. However, imbalances in immune homeostasis often facilitate microbial infection. Despite the wide-ranging effects of fungal toxins on health, our understanding of toxin-mediated modulation of immune responses is incomplete. This review will explore the current understanding of fungal toxins and how they contribute to the modulation of host immunity.
Unlike other forms of candidiasis, vulvovaginal candidiasis, caused primarily by the fungal pathogen
, is a disease of immunocompetent and otherwise healthy women. Despite its prevalence, the fungal ...factors responsible for initiating symptomatic infection remain poorly understood. One of the hallmarks of vaginal candidiasis is the robust recruitment of neutrophils to the site of infection, which seemingly do not clear the fungus, but rather exacerbate disease symptomatology. Candidalysin, a newly discovered peptide toxin secreted by
hyphae during invasion, drives epithelial damage, immune activation, and phagocyte attraction. Therefore, we hypothesized that Candidalysin is crucial for vulvovaginal candidiasis immunopathology. Anti-
immune responses are anatomical-site specific, as effective gastrointestinal, oral, and vaginal immunities are uniquely compartmentalized. Thus, we aimed to identify the immunopathologic role of Candidalysin and downstream signaling events at the vaginal mucosa. Microarray analysis of
-infected human vaginal epithelium
revealed signaling pathways involved in epithelial damage responses, barrier repair, and leukocyte activation. Moreover, treatment of A431 vaginal epithelial cells with Candidalysin induced dose-dependent proinflammatory cytokine responses (including interleukin 1α IL-1α, IL-1β, and IL-8), damage, and activation of c-Fos and mitogen-activated protein kinase (MAPK) signaling, consistent with fungal challenge. Mice intravaginally challenged with
strains deficient in Candidalysin exhibited no differences in colonization compared to isogenic controls. However, significant decreases in neutrophil recruitment, damage, and proinflammatory cytokine expression were observed with these strains. Our findings demonstrate that Candidalysin is a key hypha-associated virulence determinant responsible for the immunopathogenesis of
vaginitis.
The purpose of this study was to examine the performance characteristics and validity of the Patient Health Questionnaire-9 Item (PHQ-9) as a screening tool for depression among adolescents.
The ...PHQ-9 was completed by 442 youth (aged 13-17 years) who were enrolled in a large health care-delivery system and participated in a study on depression outcomes. Criterion validity and performance characteristics were assessed against an independent structured mental health interview (the Child Diagnostic Interview Schedule DISC-IV). Construct validity was tested by examining associations between the PHQ-9 and a self-report measure of functional impairment, as well as parental reports of child psychosocial impairment and internalizing symptoms.
A PHQ-9 score of 11 or more had a sensitivity of 89.5% and a specificity of 77.5% for detecting youth who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression on the DISC-IV. Receiver-operator-curve analysis revealed that the PHQ-9 had an area under the curve of 0.88 (95% confidence interval: 0.82-0.94), and the cut point of 11 was optimal for maximizing sensitivity without loss of specificity. Increasing PHQ-9 scores were significantly correlated with increasing levels of functional impairment, as well as parental report of internalizing symptoms and psychosocial problems.
Although the optimal cut point is higher among adolescents, the sensitivity and specificity of the PHQ-9 are similar to those of adult populations. The brief nature and ease of scoring of this instrument make this tool an excellent choice for providers and researchers seeking to implement depression screening in primary care settings.
Candida albicans is a fungal pathobiont, able to cause epithelial cell damage and immune activation. These functions have been attributed to its secreted toxin, candidalysin, though the molecular ...mechanisms are poorly understood. Here, we identify epidermal growth factor receptor (EGFR) as a critical component of candidalysin-triggered immune responses. We find that both C. albicans and candidalysin activate human epithelial EGFR receptors and candidalysin-deficient fungal mutants poorly induce EGFR phosphorylation during murine oropharyngeal candidiasis. Furthermore, inhibition of EGFR impairs candidalysin-triggered MAPK signalling and release of neutrophil activating chemokines in vitro, and diminishes neutrophil recruitment, causing significant mortality in an EGFR-inhibited zebrafish swimbladder model of infection. Investigation into the mechanism of EGFR activation revealed the requirement of matrix metalloproteinases (MMPs), EGFR ligands and calcium. We thus identify a PAMP-independent mechanism of immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis.
During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained ...unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from micrometers to tens of micrometers. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes.
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•Notch signaling is proportional to the contact area between cells•Cell size can bias cell fate decisions in a lateral inhibition patterning model•Modeling predicts that smaller cells are likelier to become signal producing•In the inner ear, ligand-producing hair cell precursors are smaller than neighbors
Cell geometry varies considerably between cells in almost every tissue. Shaya et al. show that Notch signaling between pairs of cells correlates with their contact area. This dependence of signaling on contact area can bias Notch-mediated cell fate decisions such as those occurring in chick inner ear development.
Inhibition of the mitochondrial permeability transition pore (MPTP) by the novel inhibitor GNX-4975 was characterized. Titration of MPTP activity in de-energized rat liver mitochondria allowed ...determination of the number of GNX-4975-binding sites and their dissociation constant (Ki). Binding sites increased in number when MPTP opening was activated by increasing Ca(2+), phenylarsine oxide (PAO) or KSCN, and decreased when MPTP opening was inhibited with bongkrekic acid (BKA) or ADP. Values ranged between 9 and 50 pmol/mg of mitochondrial protein, but the Ki remained unchanged at ∼1.8 nM when the inhibitor was added before Ca(2+) However, when GNX-4975 was added after Ca(2+) it was much less potent with a Ki of ∼140 nM. These data imply that a protein conformational change is required to form the MPTP complex and generate the GNX-4975-binding site. Occupation of the latter with GNX-4975 prevents the Ca(2+) binding that triggers pore opening. We also demonstrated that GNX-4975 stabilizes an interaction between the adenine nucleotide translocase (ANT), held in its 'c' conformation with carboxyatractyloside (CAT), and the phosphate carrier (PiC) bound to immobilized PAO. No components of the F1Fo-ATP synthase bound significantly to immobilized PAO. Our data are consistent with our previous proposal that the MPTP may form at an interface between the PiC and ANT (or other similar mitochondrial carrier proteins) when they adopt novel conformations induced by factors that sensitize the MPTP to Ca(2+). We propose that GNX-4975 binds to this interface preventing a calcium-triggered event that opens the interface into a pore.
Abstract The adverse sequalae of inadequate pain control in the burn population have been long recognised, yet control of pain remains inadequate globally. The dynamic evolution of burn pain both ...centrally and peripherally, and the many factors which influence pain perception illustrate the need for a therapeutic plan which is similarly dynamic and flexible enough to cope with the facets of background, breakthrough, procedural and post-operative pain. Regular, ongoing and documented pain assessment is key in directing this process. The family of opioid analgesics provide the backbone of analgesia to burn patients. Together, they provide an excellent range of potencies, duration of actions and routes of administration. However, they must be used judiciously as side-effects may be clinically relevant and furthermore, recent data has implicated them as being capable of inducing pain. NMDA receptor antagonist such as ketamine and gabapentin are increasingly recognised as useful adjuncts, capable of marked opiate sparing effects in this population. The simple analgesic paracetamol (acetaminophen) has both anti-pyretic and opioid-sparing properties and justly deserves its place in the pharmacological treatment of every burn patient. Non-pharmacological methods of pain control can play an important role in suitable patients but resources vary widely between units. With this review article, we have set out to give practical guidance to all healthcare professionals with examples from our practice. We have found the addition of pain specialists as an integral part of the burns multi-disciplinary team, and an environment where pain is given a high clinical priority to be invaluable in our approach to pain control.
Recent studies have delineated cancer-type-specific roles of histone 3 lysine 27 (H3K27) demethylase KDM6B/JMJD3 depending on its H3K27 demethylase activity. Here we show that KDM6B is expressed in ...multiple myeloma (MM) cells; and that shRNA-mediated knockdown and CRISPR-mediated knockout of KDM6B abrogate MM cell growth and survival. Tumor necrosis factor-α or bone marrow stromal cell culture supernatants induce KDM6B, which is blocked by IKKβ inhibitor MLN120B, suggesting that KDM6B is regulated by NF-κB signaling in MM cells. RNA-seq and subsequent ChIP-qPCR analyses reveal that KDM6B is recruited to the loci of genes encoding components of MAPK signaling pathway including ELK1 and FOS, and upregulates expression of these genes without affecting H3K27 methylation level. Overexpression of catalytically inactive KDM6B activates expression of MAPK pathway-related genes, confirming its function independent of demethylase activity. We further demonstrate that downstream targets of KDM6B, ELK1 and FOS, confer MM cell growth. Our study therefore delineates KDM6B function that links NF-κB and MAPK signaling pathway mediating MM cell growth and survival, and validates KDM6B as a novel therapeutic target in MM.
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