A Myo6 Mutation Destroys Coordination between the Myosin Heads, Revealing New Functions of Myosin VI in the Stereocilia of Mammalian Inner Ear Hair Cells

Myosin VI, found in organisms from Caenorhabditis elegans to humans, is essential for auditory and vestibular function in mammals, since genetic mutations lead to hearing impairment and vestibular dysfunction in both humans and mice. Here, we show that a missense mutation in this molecular motor in an ENU-generated mouse model, Tailchaser, disrupts myosin VI function. Structural changes in the Tailchaser hair bundles include mislocalization of the kinocilia and branching of stereocilia. Transfection of GFP-labeled myosin VI into epithelial cells and delivery of endocytic vesicles to the early endosome revealed that the mutant phenotype displays disrupted motor function. The actin-activated ATPase rates measured for the D179Y mutation are decreased, and indicate loss of coordination of the myosin VI heads or ‘gating’ in the dimer form. Proper coordination is required for walking processively along, or anchoring to, actin filaments, and is apparently destroyed by the proximity of the mutation to the nucleotide-binding pocket. This loss of myosin VI function may not allow myosin VI to transport its cargoes appropriately at the base and within the stereocilia, or to anchor the membrane of stereocilia to actin filaments via its cargos, both of which lead to structural changes in the stereocilia of myosin VI–impaired hair cells, and ultimately leading to deafness

E-NTPDases in human airways: Regulation and relevance for chronic lung diseases

Chronic obstructive lung diseases are characterized by the inability to prevent bacterial infection and a gradual loss of lung function caused by recurrent inflammatory responses. In the past decade, numerous studies have demonstrated the importance of nucleotide-mediated bacterial clearance. Their interaction with P2 receptors on airway epithelia provides a rapid ‘on-and-off’ signal stimulating mucus secretion, cilia beating activity and surface hydration. On the other hand, abnormally high ATP levels resulting from damaged epithelia and bacterial lysis may cause lung edema and exacerbate inflammatory responses. Airway ATP concentrations are regulated by ecto nucleoside triphosphate diphosphohydrolases (E-NTPDases) which are expressed on the mucosal surface and catalyze the sequential dephosphorylation of nucleoside triphosphates to nucleoside monophosphates (ATP → ADP → AMP). The common bacterial product, Pseudomonas aeruginosa lipopolysaccharide (LPS), induces an acute reduction in azide-sensitive E-NTPDase activities, followed by a sustained increase in activity as well as NTPDase 1 and NTPDase 3 expression. Accordingly, chronic lung diseases, including cystic fibrosis (CF) and primary ciliary dyskinesia, are characterized by higher rates of nucleotide elimination, azide-sensitive E-NTPDase activities and expression. This review integrates the biphasic regulation of airway E-NTPDases with the function of purine signaling in lung diseases. During acute insults, a transient reduction in E-NTPDase activities may be beneficial to stimulate ATP-mediated bacterial clearance. In chronic lung diseases, elevating E-NTPDase activities may represent an attempt to prevent P2 receptor desensitization and nucleotide-mediated lung damage

Diagenesis of archaeological bone and tooth

An understanding of the structural complexity of mineralised tissues is fundamental for exploration into the field of diagenesis. Here we review aspects of current and past research on bone and tooth diagenesis using the most comprehensive collection of literature on diagenesis to date. Environmental factors such as soil pH, soil hydrology and ambient temperature, which influence the preservation of skeletal tissues are assessed, while the different diagenetic pathways such as microbial degradation, loss of organics, mineral changes, and DNA degradation are surveyed. Fluctuating water levels in and around the bone is the most harmful for preservation and lead to rapid skeletal destruction. Diagenetic mechanisms are found to work in conjunction with each other, altering the biogenic composition of skeletal material. This illustrates that researchers must examine multiple diagenetic pathways to fully understand the post-mortem interactions of archaeological skeletal material and the burial environment

Using the M-CHAT-R/F as a Screening Measure to Detect Autism Risk in Children with Neurodevelopmental Disorders

The Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F) is a widely used parent-report screening tool to identify autism-related features in toddlers. The structured phone interview portion of the screener (i.e., Level 2) enables a closer examination of the initial parent reports (i.e., Level 1). Our research focused on the utility of the M-CHAT-R/F in screening for autism risk in toddlers with neurodevelopmental disorders. More specifically, we examined whether the phone interview is a valuable tool to clarify the initial responses. Our study investigated Angelman Syndrome (AS), Prader-Willi Syndrome (PWS), and Williams Syndrome (WS). Participants included 29 toddlers at Level 1, of which 21 were eligible for Level 2. Our final sample included 15 toddlers (AS: n=7; PWS: n=4; WS: n=4) aged 16 to 29 months. All participants completed a web-based M-CHAT-R/F, where higher scores reflected greater risk for autism concerns. We predicted that toddlers with AS and PWS would score higher than those with WS. We also predicted that the scores at Level 2 would be lower than those at Level 1, indicating the utility of the phone interview. Consistent with our predictions, preliminary results indicated that the median scores decreased from 12 to 9 for AS, from 4 to 3 for PWS, and from 5 to 2.5 for WS. Final analyses will include Wilcoxon rank-sum and one-sample median tests to look at more specific item-level responses. Our study highlights the value of the M-CHAT-R/F in autism screening and diagnosis for children with neurodevelopmental disorders

Application usability levels: A framework for tracking project product progress

The space physics community continues to grow and become both more interdisciplinary and more intertwined with commercial and government operations. This has created a need for a framework to easily identify what projects can be used for specific applications and how close the tool is to routine autonomous or on-demand implementation and operation. We propose the Application Usability Level (AUL) framework and publicizing AULs to help the community quantify the progress of successful applications, metrics, and validation efforts. This framework will also aid the scientific community by supplying the type of information needed to build off of previously published work and publicizing the applications and requirements needed by the user communities. In this paper, we define the AUL framework, outline the milestones required for progression to higher AULs, and provide example projects utilizing the AUL framework. This work has been completed as part of the activities of the Assessment of Understanding and Quantifying Progress working group which is part of the International Forum for Space Weather Capabilities Assessment