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There is a need for a straightforward, accessible and accurate pediatric test for color vision deficiency (CVD). We present and evaluate ColourSpot, a self-administered, gamified and color calibrated tablet-based app, which diagnoses CVD from age 4. Children tap colored targets with saturations that are altered adaptively along the three dichromatic confusion lines. Two cohorts (Total, N = 772; Discovery, N = 236; Validation, N = 536) of 4-7-year-old boys were screened using the Ishihara test for Unlettered Persons and the Neitz Test of Color Vision. ColourSpot was evaluated by testing any child who made an error on the Ishihara Unlettered test alongside a randomly selected control group who made no errors. Psychometric functions were fit to the data and "threshold ratios" were calculated as the ratio of tritan to protan or deutan thresholds. Based on the threshold ratios derived using an optimal fitting procedure that best categorized children in the discovery cohort, ColourSpot showed a sensitivity of 1.00 and a specificity of 0.97 for classifying CVD against the Ishihara Unlettered in the independent validation cohort. ColourSpot was also able to categorize individuals with ambiguous results on the Ishihara Unlettered. Compared to the Ishihara Unlettered, the Neitz Test generated an unacceptably high level of false positives. ColourSpot is an accurate test for CVD, which could be used by anyone to diagnose CVD in children from the start of their education. ColourSpot could also have a wider impact: its interface could be adapted for measuring other aspects of children's visual performance., (© 2021. The Author(s).)

In anomalous trichromacy, the color signals available from comparing the activities of the two classes of cone sensitive in the medium and long wavelength parts of the spectrum are much reduced from those available in normal trichromacy, and color discrimination thresholds along the red-green axis are correspondingly elevated. Yet there is evidence that suprathreshold color perception is relatively preserved; this has led to the suggestion that anomalous trichromats post-receptorally amplify their impoverished red-green signals. To test this idea, we measured chromatic discrimination from white and from saturated red and green pedestals. If there is no post-receptoral compensation, the anomalous trichromat's loss of chromatic contrast will apply equally to the pedestal and to the test color. Coupled with a compressively nonlinear neural representation of saturation, this means that a given pedestal contrast will cause a smaller than normal modulation of discrimination sensitivity. We examined cases where chromatic pedestals impair the color discrimination of normal trichromatic observers. As predicted, anomalous observers experienced less impairment than normal trichromats, though they remained less sensitive than normal trichromats. Although the effectiveness of chromatic pedestals in impairing color discrimination was less for anomalous than for normal trichromats, the chromatic pedestals were more effective for anomalous observers than would be expected if the anomalous post-receptoral visual system were the same as in normal trichromacy; the hypothesis of zero compensation can be rejected. This might suggest that the effective contrast of the pedestal is post-receptorally amplified. But on closer analysis, the results do not support candidate simple models involving post-receptoral compensation either., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Since at least the 17 th century there has been the idea that there are four simple and perceptually pure "unique" hues: red, yellow, green, and blue, and that all other hues are perceived as mixtures of these four hues. However, sustained scientific investigation has not yet provided solid evidence for a neural representation that separates the unique hues from other colors. We measured event-related potentials elicited from unique hues and the 'intermediate' hues in between them. We find a neural signature of the unique hues 230 ms after stimulus onset at a post-perceptual stage of visual processing. Specifically, the posterior P2 component over the parieto-occipital lobe peaked significantly earlier for the unique than for the intermediate hues (Z = -2.9, p = 0.004). Having identified a neural marker for unique hues, fundamental questions about the contribution of neural hardwiring, language and environment to the unique hues can now be addressed., Competing Interests: The authors declare no competing financial interests.

The peripheral nerve contains three barriers which include the blood-nerve barrier consisting of endoneurial vessels and the perineurium as well as autotypic junctions in Schwann cells. The perineurium prevents diffusion of perineurally injected drugs that can be used for selective regional pain control. It is composed of a basal membrane and layers of perineurial cells sealed by tight junction proteins like claudin-1. Claudin-1 expression and barrier function are regulated via low-density lipoprotein receptor-related protein (LRP-1). Perisciatic application of recombinant tissue plasminogen activator (rtPA) or the catalytically inactive rtPAi - both agonists of LRP-1 - reduced claudin-1 mRNA and protein expression in the rat nerve. This facilitated an increase of nociceptive thresholds after local application of hydrophilic opioids or the voltage gated sodium channel blocker (NaV1.7) ProToxin-II without apparent nerve toxicity. RtPA-induced barrier opening was mediated by LRP-1 and intracellularly by Erk phosphorylation. In silico, microRNA (miR)-rno-29b-2-5p and rno-miR-183-5p were identified as potential regulators of claudin-1 transcription in the rat. RtPA application increased miR-183-5p in the sciatic nerve. MiR-183-5p mimics functionally opened the perineurium and downregulated claudin-1 expression in vivo. In vitro, hsa-miR-183-3p mimics reduced claudin-1 expression in human HT-29/B6 cells. Overall, rtPA regulates perineurial barrier tightness via LRP-1, Erk phosphorylation and miR-183-5p/3p. This mechanism might serve as a new principle to facilitate drug delivery to peripheral nerves in humans., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

To shed light on the perceptual basis of the color white, we measured settings of unique white in a dark surround. We find that settings reliably show more variability in an oblique (blue-yellow) direction in color space than along the cardinal axes of the cone-opponent mechanisms. This is against the idea that white perception arises at the null point of the cone-opponent mechanisms, but one alternative possibility is that it occurs through calibration to the visual environment. We found that the locus of maximum variability in settings lies close to the locus of natural daylights, suggesting that variability may result from uncertainty about the color of the illuminant. We tested this by manipulating uncertainty. First, we altered the extent to which the task was absolute (requiring knowledge of the illumination) or relative. We found no clear effect of this factor on the reduction in sensitivity in the blue-yellow direction. Second, we provided a white surround as a cue to the illumination or left the surround dark. Sensitivity was selectively worse in the blue-yellow direction when the surround was black than when it was white. Our results can be functionally related to the statistics of natural images, where a greater blue-yellow dispersion is characteristic of both reflectances (where anisotropy is weak) and illuminants (where it is very pronounced). Mechanistically, the results could suggest a neural signal responsive to deviations from the blue-yellow locus or an adaptively matched range of contrast response functions for signals that encode different directions in color space.

For anomalous trichromats, threshold contrasts for color differences captured by the L and M cones and their anomalous analogs are much higher than for normal trichromats. The greater spectral overlap of the cone sensitivities reduces chromatic contrast both at and above threshold. But above threshold, adaptively nonlinear processing might compensate for the chromatically impoverished photoreceptor inputs. Ratios of sensitivity for threshold variations and for color appearance along the two cardinal axes of MacLeod-Boynton chromaticity space were calculated for three groups: normals (N = 15), deuteranomals (N = 9), and protanomals (N = 5). Using a four-alternative forced choice (4AFC) task, threshold sensitivity was measured in four color-directions along the two cardinal axes. For the same participants, we reconstructed perceptual color spaces for the positions of 25 hues using multidimensional scaling (MDS). From the reconstructed color spaces we extracted "color difference ratios," defined as ratios for the size of perceived color differences along the L/(L + M) axis relative to those along the S/(L + M) axis, analogous to "sensitivity ratios" extracted from the 4AFC task. In the 4AFC task, sensitivity ratios were 38% of normal for deuteranomals and 19% of normal for protanomals. Yet, in the MDS results, color difference ratios were 86% of normal for deuteranomals and 67% of normal for protanomals. Thus, the contraction along the L/(L + M) axis shown in the perceptual color spaces of anomalous trichromats is far smaller than predicted by their reduced sensitivity, suggesting that an adaptive adjustment of postreceptoral gain may magnify the cone signals of anomalous trichromats to exploit the range of available postreceptoral neural signals., (© 2014 ARVO.)

The blood-nerve barrier consists of the perineurium and endoneurial vessels. The perineurial barrier is composed of a basal membrane and a layer of perineurial cells sealed by tight junction proteins preventing e.g. application of analgesics for selective regional pain control. One of the barrier-sealing proteins in the blood-nerve barrier is claudin-1. Therefore, the claudin-1-peptidomimetics (C1C2), derived from the first extracellular loop (ECL1) on claudin-1 was developed. In this study, we further evaluated the expression of tight junction proteins in the perineurium in Wistar rats and characterized the specificity, in vivo applicability, mechanism of action as well as the biocompatibility of C1C2. In the perineurium, claudin-19, tricellulin and ZO-1, but no claudin-2, 3, 8 and -11 were expressed. C1C2 specifically bound to the ECL1 of claudin-1 and fluorescent 5,6-carboxytetramethylrhodamine-C1C2 was rapidly internalized. Opening the perineurium with C1C2 reduced the mRNA and protein expression of claudin-1 and increased small and macromolecule permeability into the peripheral nerve. Application of C1C2 facilitated regional analgesia using μ-opioid receptor agonists like DAMGO or morphine without motor impairment in naïve rats as well as rats with hind paw inflammation. In contrast the control peptide C2C2 derived from ECL1 on claudin-2 did neither open the barrier nor facilitated opioid-mediated regional analgesia. C1C2 delivery was well tolerated and caused no morphological and functional nerve damage. C1C2 effects could be reversed by interference with the wnt-signal-transduction pathway, specifically the homeobox transcription factor cdx2, using a glycogen-synthase-kinase-3 inhibitor. In summary, we describe the composition of and a pathway to open the perineurial barrier employing a peptide to deliver hydrophilic substances to the peripheral nerve., (Copyright © 2014 Elsevier B.V. All rights reserved.)

HIV retinopathy is the most common non-infectious complication in the eyes of HIV-positive individuals. Oncotic lesions in the retinal nerve fiber layer, referred to as cotton wool spots (CWS), and intraretinal (IR) hemorrhages are frequently observed but are not unique to this pathology. HIV-positive patients have impaired color vision and contrast sensitivity, which worsens with age. Evidence of inner-retinal lesions and damage have been documented ophthalmoscopically, however their long term structural effect has not been investigated. It has been hypothesized that they may be partially responsible for loss of visual function and visual field. In this study we utilized clinical data, retinal imaging and transcriptomics approaches to comprehensively interrogate non-infectious HIV retinopathy. The methods employed encompassed clinical examinations, fundus photography, indirect ophthalmoscopy, Farmsworth-Munsell 100 hue discrimination testing and Illumina BeadChip analyses. Here we show that changes in the outer retina, specifically in the retinal pigment epithelium (RPE) and photoreceptor outer segments (POS) contribute to vision changes in non-infectious HIV retinopathy. We find that in HIV-positive retinae there is an induction of rhodopsin and other transcripts (including PDE6A, PDE6B, PDE6G, CNGA1, CNGB1, CRX, NRL) involved in visual transduction, as well as structural components of the rod photoreceptors (ABCA4 and ROM1). This is consistent with an increased rate of renewal of rod outer segments induced via increased phagocytosis by HIV-infected RPE previously reported in culture. Cone-specific transcripts (OPN1SW, OPN1LW, PDE6C, PDE6H and GRK7) are uniformly downregulated in HIV positive retina, likely due to a partial loss of cone photoreceptors. Active cotton wool spots and intraretinal hemorrhages (IRH) may not affect photoreceptors directly and the interaction of photoreceptors with the aging RPE may be the key to the progressive vision changes in HIV-positive patients.