Natural scene VR provided relaxation both objectively and subjectively, and scene preference had a significant effect on mood and perception of scene quality. VR may enable relaxation for people living in isolated confined environments, particularly when matched to personal preferences.Anderson AP, Mayer MD, Fellows AM, Cowan DR, Hegel MT, Buckey JC. Relaxation with immersive natural scenes presented using virtual reality. Aerosp Med Hum Perform. 2017; 88(6):520526.

The cystic fibrosis transmembrane conductance regulator (CFTR)1 is an epithelial chloride channel mutated in patients with cystic fibrosis. Its expression and functional interactions in the apical membrane are regulated by several PDZ (PSD-95, discs large, zonula occludens-1) proteins, which mediate protein-protein interactions, typically by binding C-terminal recognition motifs. In particular, the CFTR-associated ligand (CAL) limits cell-surface levels of the most common diseaseassociated mutant ΔF508-CFTR. CAL also mediates degradation of wild-type CFTR, targeting it to lysosomes following endocytosis. Nevertheless, wild-type CFTR survives numerous cycles of uptake and recycling. In doing so, how does it repeatedly avoid CAL-mediated degradation? One mechanism may involve competition between CAL and other PDZ proteins including Na + /H + Exchanger-3 Regulatory Factors 1 and 2 (NHERF1 and NHERF2), which functionally stabilize cell-surface CFTR. Thus, to understand the biochemical basis of WT-CFTR persistence, we need to know the relative affinities of these partners. However, no quantitative binding data are available for CAL or the individual NHERF2 PDZ domains, and published estimates for the NHERF1 PDZ domains conflict. Here we demonstrate that the affinity of the CAL PDZ domain for the CFTR C-terminus is much weaker than those of NHERF1 and NHERF2 domains, enabling wild-type CFTR to avoid premature entrapment in the lysosomal pathway. At the same time, CAL's affinity is evidently sufficient to capture and degrade more rapidly cycling mutants, such as ΔF508-CFTR. The relatively weak affinity of the CAL:CFTR interaction may provide a pharmacological window for stabilizing rescued ΔF508-CFTR in patients with cystic fibrosis.CFTR is a cAMP-activated, ATP-gated chloride channel. It plays a central role in maintaining fluid and ion homeostasis in epithelial tissues and is mutated in patients with cystic fibrosis (CF) (1). Although CFTR is subject to rapid endocytosis (2), this appears to be coupled with a highly efficient constitutive recycling mechanism (e.g refs. 3,4). As a result, mature CFTR exhibits a long functional half-life (5,6), requiring individual molecules to cycle through the endocytic pathway dozens or even hundreds of times. † This work was supported in part by grants from the Cystic Fibrosis Foundation (MADDEN06P0 and STANTO97R0) and the NIH (grants P20-RR018787 from the Institutional Development Award (IDeA) Program of the NCRR and R01-DK075309 from NIDDK). P.B. was supported by the Deutsche Forschungsgemeinschaft (DFG grant VO 885/3-1). 1 The abbreviations used are: CFTR, cystic fibrosis transmembrane conductance regulator; PDZ, PSD-95, discs large, zonula occludens-1; CAL, CFTR-Associated Ligand; NHERF1, Na + /H + Exchanger-3 Regulatory Factor-1; NHERF2, Na + /H + Exchanger-3 Regulatory Factor-2; CF, cystic fibrosis; DTT, dithiothreitol; TCEP, Tris(2-carboxyethyl)phosphine hydrochloride; SPR, surface-plasmon resonance; ITC, isothermal titration calorimetry; FP, fluorescence polarizatio...

Objectives Abnormal hearing tests have been noted in HIV-infected patients in several studies, but the nature of the hearing deficit has not been clearly defined. We performed a cross-sectional study of both HIV+ and HIV− individuals in Tanzania using an audiological test battery. We hypothesized that HIV+ adults would have a higher prevalence of abnormal central and peripheral hearing test results compared to HIV− controls. Additionally, we anticipated that the prevalence of abnormal hearing assessments would increase with anti-retroviral therapy (ART) use, and treatment for tuberculosis (TB). Design Pure-tone thresholds, distortion product otoacoustic emissions (DPOAEs), tympanometry, and a gap detection test were performed using a laptop-based hearing testing system on 751 subjects (100 HIV− in the U.S., plus 651 in Dar es Salaam Tanzania including 449 HIV+ [130 ART− and 319 ART+], and 202 HIV−, subjects. No U.S. subjects had a history of TB treatment. In Tanzania, 204 of the HIV+, and 23 of the HIV−, subjects had a history of TB treatment. Subjects completed a video and audio questionnaire about their hearing as well as a health history questionnaire. Results HIV+ subjects had reduced DPOAE levels compared to HIV− subjects, but their hearing thresholds, tympanometry results, and gap detection thresholds were similar. Within the HIV+ group, those on ART reported significantly greater difficulties understanding speech-in-noise, and were significantly more likely to report that they had difficulty understanding speech than the ART− group. The ART+ group had a significantly higher mean gap detection threshold compared to the ART− group. No effects of TB treatment were seen. Conclusions The fact that the ART+/ART− groups did not differ in measures of peripheral hearing ability (DPOAEs, thresholds), or middle ear measures (tympanometry), but that the ART+ group had significantly more trouble understanding speech and higher gap detection thresholds, indicates a central processing deficit. These data suggest that: (a) hearing deficits in HIV+ individuals could be a central nervous system (CNS) side effect of HIV infection, (b) certain ART regimens might produce CNS side effects that manifest themselves as hearing difficulties, and/or (c) some ART regimens may treat CNS HIV inadequately, perhaps due to insufficient CNS drug levels, which is reflected as a central hearing deficit. Monitoring of central hearing parameters could be used to track central effects of either HIV or ART.

PDZ domains are ubiquitous peptide-binding modules that mediate protein-protein interactions in a wide variety of intracellular trafficking and localization processes. These include the pathways that regulate the membrane trafficking and endocytic recycling of the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial chloride channel mutated in patients with cystic fibrosis. Correspondingly, a number of PDZ proteins have now been identified that directly or indirectly interact with the C terminus of CFTR. One of these is CAL, whose overexpression in heterologous cells directs the lysosomal degradation of WT-CFTR in a dose-dependent fashion and reduces the amount of CFTR found at the cell surface. Here, we show that RNA interference targeting endogenous CAL specifically increases cell-surface expression of the disease-associated ⌬F508-CFTR mutant and thus enhances transepithelial chloride currents in a polarized human patient bronchial epithelial cell line. We have reconstituted the CAL-CFTR interaction in vitro from purified components, demonstrating for the first time that the binding is direct and allowing us to characterize its components biochemically and biophysically. To test the hypothesis that inhibition of the binding site could also reverse CAL-mediated suppression of CFTR, a three-dimensional homology model of the CAL⅐CFTR complex was constructed and used to generate a CAL mutant whose binding pocket is correctly folded but has lost its ability to bind CFTR. Although produced at the same levels as wild-type protein, the mutant does not affect CFTR expression levels. Taken together, our data establish CAL as a candidate therapeutic target for correction of post-maturational trafficking defects in cystic fibrosis.

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