Cone Function Research Articles

Evaluation of electroretinography (ERG) parameters as a biomarker for ADHD

BackgroundThe retina is recognized as an accessible part of the brain due to their common embryonic origin. The electroretinogram (ERG) has proven to be a valuable tool for detecting schizophrenia and bipolarity. We therefore investigated its ability to detect ADHD. MethodsThe cone and rod luminance response functions of the ERG were recorded in 26 ADHD subjects (17 women and 9 men) and 25 controls (16 women and 9 men). ResultsNo significant differences were found between the mixed groups, but sexual dysmorphia was observed in the significant results. In males, a significant prolonged cone a-wave latency was observed in the ADHD group. In females, we observed a significant decrease in the cone a- and b-wave amplitudes and a trend for a prolonged cone b-wave latency as well as a higher scotopic mixed rod-cone a-wave in the ADHD group. ConclusionThe data obtained in this study show the potential of the ERG to detect ADHD, warranting further large-scale studies.

Representation of relative sheaf cohomology

Abstract We study the cohomology theory of sheaf complexes for open embeddings of topological spaces and related subjects. The theory is situated in the intersection of the general Čech theory and the theory of derived categories. That is to say, on the one hand the cohomology is described as the relative cohomology of the sections of the sheaf complex, which appears naturally in the theory of Čech cohomology of sheaf complexes. On the other hand it is interpreted as the cohomology of a complex dual to the mapping cone of a certain morphism of complexes in the theory of derived categories. We prove a “relative de Rham-type theorem” from the above two viewpoints. It says that, in the case the complex is a soft or fine resolution of a certain sheaf, the cohomology is canonically isomorphic with the relative cohomology of the sheaf. Thus the former provides a handy way of representing the latter. Along the way we develop various theories and establishes canonical isomorphisms among the cohomologies that appear therein. The second viewpoint leads to a generalization of the theory to the case of cohomology of sheaf morphisms. Some special cases together with applications are also indicated. Particularly notable is the application of the Dolbeault complex case to the Sato hyperfunction theory and other problems in algebraic analysis.

Chromophore supply modulates cone function and survival in retinitis pigmentosa mouse models

Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the retina by cone photoreceptors, which are gradually lost in RP, often as bystanders in a disease process that initiates in their neighboring rod photoreceptors. Using physiological assays, we investigated the timing of cone electroretinogram (ERG) decline in RP mouse models. A correlation between the time of loss of the cone ERG and the loss of rods was found. To investigate a potential role of the visual chromophore supply in this loss, mouse mutants with alterations in the regeneration of the retinal chromophore, 11-cis retinal, were examined. Reducing chromophore supply via mutations in Rlbp1 or Rpe65 resulted in greater cone function and survival in a RP mouse model. Conversely, overexpression of Rpe65 and Lrat, genes that can drive the regeneration of the chromophore, led to greater cone degeneration. These data suggest that abnormally high chromophore supply to cones upon the loss of rods is toxic to cones, and that a potential therapy in at least some forms of RP is to slow the turnover and/or reduce the level of visual chromophore in the retina.

Novel femur-like multimodal ultrahigh strength structure with superb freedom based on the improvement strategy of curvature fabricated by additive manufacturing

Based on the microstructure of biological femur, the femur-like multimodal surface structures are designed. But they exhibit fracture behavior when the porosity changes, resulting in structural failure. The high curvature surface factor is introduced to improve the fracture behavior of the biomimetic surface structure. Combine the high curvature surface factor to construct novel biomimetic homogenized surface structures. Novel radial gradient surface structures and axial gradient surface structures are designed based on the construction concept of cone functions and linear functions gradients. Theoretical, experimental and numerical methods are used to investigate the mechanical properties of novel biomimetic multimodal surface structures. Euler theory states that the properties of lattice structures are determined by the relative density of structures. The load distribution in the radially gradient structure is uniform, and the deformation mode presents overall failure, which can achieve better resistance and dissipation of the load. The deformation modes of axial gradient structures present layered failure. The underlying mechanism of the difference in mechanical properties of biomimetic multimodal structures is explained in detail. It’s very important significance for targeted application in protective engineering.

HSP90α is needed for the survival of rod photoreceptors and regulates the expression of rod PDE6 subunits

Heat shock protein 90 (HSP90) is an abundant molecular chaperone that regulates the stability of a small set of proteins essential in various cellular pathways. Cytosolic HSP90 has two closely related paralogs: HSP90α and HSP90β. Due to the structural and sequence similarities of cytosolic HSP90 paralogs, identifying the unique functions and substrates in the cell remains challenging. In this article, we assessed the role of HSP90α in the retina using a novel HSP90α murine knockout model. Our findings show that HSP90α is essential for rod photoreceptor function but was dispensable in cone photoreceptors. In the absence of HSP90α, photoreceptors developed normally. We observed rod dysfunction in HSP90α knockout at 2months with the accumulation of vacuolar structures, apoptotic nuclei, and abnormalities in the outer segments. The decline in rod function was accompanied by progressive degeneration of rod photoreceptors that was complete at 6months. The deterioration in cone function and health was a "bystander effect" that followed the degeneration of rods. Tandem mass tag proteomics showed that HSP90α regulates the expression levels of <1% of the retinal proteome. More importantly, HSP90α was vital in maintaining rod PDE6 and AIPL1 cochaperone levels in rod photoreceptor cells. Interestingly, cone PDE6 levels were unaffected. The robust expression of HSP90β paralog in cones likely compensates for the loss of HSP90α. Overall, our study demonstrated the critical need for HSP90α chaperone in the maintenance of rod photoreceptors and showed potential substrates regulated by HSP90α in the retina.

Generation of Synthetic CPTs with Access to Limited Geotechnical Data for Offshore Sites

The initial design phase for offshore wind farms does not require complete geotechnical mapping and individual cone penetration testing (CPT) for each expected turbine location. Instead, background information from open source studies and previous historic records for geology and seismic data are typically used at this early stage to develop a preliminary ground model. This study focuses specifically on the interpolation and extrapolation of cone penetration test (CPT) data. A detailed methodology is presented for the process of using a limited number of CPTs to characterise the geotechnical behavior of an offshore site using artificial neural networks. In the presented study, the optimised neural network achieved a predictive error of 0.067. Accuracy is greatest at depths of less than 10 m. The pitfalls of using machine learning for geospatial interpolation are explained and discussed.

Imaging Biomarkers of Mesopic and Dark-Adapted Macular Functions in Eyes With Treatment-Naïve Mild Diabetic Retinopathy

To investigate the relationship between imaging biomarkers and mesopic and dark-adapted (i.e. scotopic) functions in patients with firstly detected treatment-naïve mild diabetic retinopathy (DR) and normal visual acuity. Prospective cross-sectional study. In this study, 60 patients with treatment-naïve mild DR (ETDRS 20-35) and 30 healthy controls underwent microperimetry, structural optical coherence tomography (OCT) and OCT angiography (OCTA). The foveal mesopic (22.4±4.5 dB and 25.8±2.0 dB, p=0.005), parafoveal mesopic (23.2±3.8 and 25.8±1.9, p<0.0001), and parafoveal dark-adapted (21.1±2.8 dB and 23.2±1.9 dB, p=0.003) sensitivities were reduced in DR eyes. For the foveal mesopic sensitivity, the regression analysis showed a significant topographical association with choriocapillaris flow deficits percentage (CC FD%; β: -0.234, p=0.046) and ellipsoid zone (EZ) "normalized" reflectivity (β: 0.282, p=0.048). The parafoveal mesopic sensitivity was significantly topographically associated with inner retinal thickness (β: 0.253, p=0.035), deep capillary plexus (DCP) vessel length density (VLD; β: 0.542, p=0.016), CC FD% (β: -0.312, p=0.032), and EZ "normalized" reflectivity (β: 0.328, p=0.031). Similarly, the parafoveal dark-adapted sensitivity was topographically associated with inner retinal thickness (β: 0.453, p=0.021), DCP VLD (β: 0.370, p=0.030), CC FD% (β: -0.282, p=0.048), and EZ "normalized" reflectivity (β: 0.295, p=0.042). In treatment-naïve mild DR eyes, both rod and cone functions are affected and they are associated with both DCP and CC flow impairment, which suggests that a macular hypoperfusion at these levels might implicate a reduction in photoreceptor function. The "normalized" EZ reflectivity may be a valuable structural biomarker for assessing the photoreceptor function in DR.

Very well–covered graphs by Betti splittings

A very well–covered graph is an unmixed graph without isolated vertices such that the height of its edge ideal is half of the number of vertices. We study these graphs by means of Betti splittings and mapping cone constructions. We show that the cover ideals of Cohen–Macaulay very well–covered graphs are splittable. As a consequence, we compute explicitly the minimal graded free resolution of the cover ideals of such a class of graphs and prove that these graphs have homological linear quotients. Finally, we conjecture the same is true for each power of the cover ideal of a Cohen–Macaulay very well–covered graph, and settle it in the bipartite case.

Complete L∞-algebras and their homotopy theory

We analyze a model for the homotopy theory of complete filtered L∞-algebras intended for applications in algebraic and algebro-geometric deformation theory. We provide an explicit proof of an unpublished result of E. Getzler which states that the category Lieˆ∞ of such L∞-algebras and filtration-preserving ∞-morphisms admits the structure of a category of fibrant objects (CFO) for a homotopy theory. Novel applications of our approach include explicit models for homotopy pullbacks, and an analog of Whitehead's Theorem: under some mild conditions, every filtered L∞-quasi-isomorphism in Lieˆ∞ has a filtration preserving homotopy inverse. Also, we show that the simplicial Maurer–Cartan functor, which assigns a Kan simplicial set to each L∞-algebra in Lieˆ∞, is an exact functor between the respective CFOs. Finally, we provide an obstruction theory for the general problem of lifting a Maurer-Cartan element through an ∞-morphism. The obstruction classes reside in the associated graded mapping cone of the corresponding tangent map.

Correlation between hyperreflective foci and visual function testing in eyes with intermediate age-related macular degeneration

BackgroundTo investigate the relationship between intraretinal hyperreflective foci (HRF) and visual function in intermediate age-related macular degeneration (iAMD).MethodsRetrospective, cross-sectional study. iAMD patients underwent spectral domain optical coherence tomography (SD-OCT) imaging and vision function testing: normal luminance best corrected visual acuity (VA), low luminance VA (LLVA), quantitative contrast sensitivity function (qCSF), low luminance qCSF (LLqCSF), and mesopic microperimetry. Each OCT volume was graded for the presence and number of HRF. Each HRF was graded for: separation from the retinal pigment epithelium (RPE), above drusen, and shadowing. Central drusen volume was calculated by the built-in functionality of the commercial OCT software after manual segmentation of the RPE and Bruch’s membrane.ResultsHRF group: 11 eyes; 9 patients; mean age 75.7 years. No-HRF group: 11 eyes; 10 patients; mean age 74.8 years. In linear mixed effect model adjusting for cube-root transformed drusen volume, HRF group showed statistically significant worse VA, LLVA, LLqCSF, and microperimetry. HRF group showed worse cone function, as measured by our pre-defined multicomponent endpoint, incorporating LLVA, LLqCSF and microperimetry (p = 0.018). For eyes with HRF, # of HRF did not correlate with any functional measures; however, % of HRF separated from RPE and # of HRF that created shadowing were statistically associated with low luminance deficit (LLD).ConclusionsThe association between the presence of HRF and worse cone visual function supports the hypothesis that eyes with HRF have more advanced disease.

Blue cone monochromacy and gene therapy

Blue cone monochromacy (BCM) is a congenital vision disorder characterized by complete loss or severely reduced long- and middle-wavelength cone function, caused by mutations in the OPN1LW/OPN1MW gene cluster on the X-chromosome. BCM patients typically suffer from poor visual acuity, severely impaired color discrimination, myopia, and nystagmus. In this review, we cover the genetic causes of BCM, clinical features of BCM patients, genetic testing, and clinical outcome measurements for future BCM clinical trials. However, our emphasis is on detailing the animal models for BCM and gene therapy using adeno-associated vectors (AAV). We describe two mouse models resembling the two most common causes of BCM, current progress in proof-of-concept studies to treat BCM with deletion mutations, the challenges we face, and future directions.

Design of Quadruple Offset Butterfly Valve Used in Power Plants

The elliptical disc is a specific characteristic of a triple offset butterfly valve (TOBV), but the structure of the elliptical disc leads to a non-uniform distribution of contact at the closing position with non-uniform wear. On the other hand, the continuous processing of elliptical sections to finish the entire disc contour is expensive compared to the processing of a circular section. In the present study, to improve the above disadvantages of an elliptical disc, an elliptic cone function was established to describe the quadruple butterfly valve (QOBV) disc shape, which has a circular section disc. In addition, some designs of a fixed thickness (7 mm) laminated seal for good sealing were proved. Sealing performance simulations were carried out using the thermal–structural coupling analysis. The best design of the QOBV showed that the maximum contact pressure was 37.2% lower than the TOBV using the seven-way laminated seal layers (thickness of A240–316 stainless and graphite was 1.3 mm and 0.6 mm, respectively). Compared to TOBV, the QOBV disc operation during the opening and closing process was faster and smoother. The disc can be applied widely to various industrial fields, engine exhaust systems, and turbine and power plants under severe environments.

Reduced inspired oxygen decreases retinal superoxide radicals and promotes cone function and survival in a model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is caused by many different mutations that promote the degeneration of rod photoreceptors and have no direct effect on cones. After the majority of rods have died cone photoreceptors begin to slowly degenerate. Oxidative damage contributes to cone cell death and it has been hypothesized that tissue hyperoxia due to reduced oxygen consumption from the loss of rods is what initiates oxidative stress. Herein, we demonstrate in animal models of RP that reduction of retinal hyperoxia by reducing inspired oxygen to continuous breathing of 11% O2 reduced the generation of superoxide radicals in the retina and preserved cone structure and function. These data indicate that retinal hyperoxia is the initiating event that promotes oxidative damage, loss of cone function, and cone degeneration in the RP retina.

USH2A Gene Mutations in Rabbits Lead to Progressive Retinal Degeneration and Hearing Loss.

Mutations in USH2A gene are responsible for the greatest proportion of the Usher Syndrome (USH) population, among which more than 30% are frameshift mutations on exon 13. A clinically relevant animal model has been absent for USH2A-related vision loss. Here we sought to establish a rabbit model carrying USH2A frameshift mutation on exon 12 (human exon 13 equivalent). CRISPR/Cas9 reagents targeting the rabbit USH2A exon 12 were delivered into rabbit embryos to produce an USH2A mutant rabbit line. The USH2A knockout animals were subjected to a series of functional and morphological analyses, including acoustic auditory brainstem responses, electroretinography, optical coherence tomography, fundus photography, fundus autofluorescence, histology, and immunohistochemistry. The USH2A mutant rabbits exhibit hyper-autofluorescent signals on fundus autofluorescence and hyper-reflective signals on optical coherence tomography images as early as 4 months of age, which indicate retinal pigment epithelium damage. Auditory brainstem response measurement in these rabbits showed moderate to severe hearing loss. Electroretinography signals of both rod and cone function were decreased in the USH2A mutant rabbits starting from 7 months of age and further decreased at 15 to 22 months of age, indicating progressive photoreceptor degeneration, which is confirmed by histopathological examination. Disruption of USH2A gene in rabbits is sufficient to induce hearing loss and progressive photoreceptor degeneration, mimicking the USH2A clinical disease. To our knowledge, this study presents the first mammalian model of USH2 showing the phenotype of retinitis pigmentosa. This study supports the use of rabbits as a clinically relevant large animal model to understand the pathogenesis and to develop novel therapeutics for Usher syndrome.

Assessment of Scotopic Function in Rod-Cone Inherited Retinal Degeneration With the Scotopic Macular Integrity Assessment.

The scotopic macular integrity assessment (S-MAIA) can perform scotopic assessment to detect localized changes to scotopic rod and cone function. This study is an exploratory investigation of the feasibility of using the S-MAIA in a rod-cone dystrophy population to identify the pattern of loss in scotopic photoreceptor function. Twenty patients diagnosed with a rod-cone dystrophy underwent visual acuity testing, full-field stimulus threshold assessment, and multiple S-MAIA tests after dark adaptation periods of 20 minutes and 45 minutes performed separately. Only right eyes were tested. Three tests were performed following a learning test. A Bland-Altman analysis was used to assess repeatability and agreement between tests after the two time periods. Spatial interpolation maps were created from the group plots to display the pattern of rod and cone loss. Learning effects took place between testing sessions 1 and 2 but not 2 and 3. Limits of agreement were larger in the patient eyes than control eyes, but within previously reported values. Using longer adaptation time of 45 minutes did not offer a significant advantage over 20 minutes. Patterns for the cyan and red sensitivities were different, indicating different patterns of loss for rods and cones. A dark adaptation time of 20 minutes before testing is sufficient for thresholding. The S-MAIA is suitable for use in patients with a logarithm of the minimum angle of resolution vision of at least 0.7 and provides a viable outcome measure for patients with rod-cone dystrophies and preserved central vision. The spatial information about scotopic function from the S-MAIA provides information about disease processes and progression. There is a need for scotopic measures for use in clinical trials. Scotopic microperimetry works well in patients with early disease, allowing the extension of recruitment criteria for novel therapies of rod-cone dystrophies.

Using cGMP analogues to modulate photoreceptor light sensitivity.

For many hereditary degenerative diseases, like retinitis pigmentosa, the primary degeneration of rod photoreceptors leads to a secondary loss of cones and eventually to blindness. The pathophysiological mechanism is very often characterized by an increase of cGMP level in rods. Thus, rod degeneration is mainly triggered by an over-activation of cyclic nucleotide-gated (CNG) channels and excessive Ca2+ influx. While targeting of CNG channels was already proposed for therapeutic purposes, thus far, it has not been possible to selectively inhibit rod CNG channels without compromising cone function. Here, we present a novel strategy, based on a combination of cGMP analogues, which enables the selective modulation of rod photoreceptor activity. This approach was first tested by means of the patch-clamp technique on retinal CNG channels, heterologously expressed in Xenopus oocytes and further confirmed by micro-electroretinography recordings on wild-type mouse retina. The cGMP-analogues mixture contained a CNG-channel inhibitor (Rp-8-Br-PET-cGMPS) and a CNG-channel activator (8-pCPT-cGMP). While Rp-8-Br-PET-cGMPS, when applied alone, behaved as a partial agonist and inhibited both cone and rod CNG channels equally, 8-pCPT-cGMP behaved as a very potent agonist and showed a strong concentration-dependent cone selectivity. Co-application of both compounds inhibited rod CNG channels and preserved cone functionality under both physiological and pathological cGMP levels. While the kinetics of rod channels was not influenced by this treatment, the deactivation of cone channels was slowed down. Surprisingly, this aspect did not affect the physiological cone responsiveness to light, indicating possible intracellular compensatory mechanisms. In conclusion, by delaying primary rods degeneration, this strategy shields the healthy cones and thus may either postpone the onset or slow down the disease development. Beyond the treatment of retinal diseases, using cGMP analogues with desired properties may elegantly address the isoform-specificity problem in future pharmacological therapies of related diseases.

CKAP5 enables seeding of actin bundles by exploratory microtubules.

Neuronal growth cones are cellular structures responsible for neuronal guidance in response to the cues presented to the cell from its surrounding. The function of the growth cones is heavily dependent on the cytoskeleton. Actin filaments in the form of networks and bundles are present at the periphery of the growth cone. Microtubule bundles are located in the central domain from which individual exploratory microtubules grow out towards the cell periphery. Recently, CKAP5 (in human, or its Xenopus and Drosophila equivalent, XMAP215 and MSMP, respectively) has been reported to play a role in mediating cross-talk between microtubules and actin filaments in growth cones. However, the molecular mechanism of this process is unknown. Here, we found in a reconstituted system that CKAP5 enables seeding of prevailing actin bundles by dynamic microtubules. We observed CKAP5 binding to microtubules with higher affinity than to single actin filaments. CKAP5 bound to the microtubule lattice can recruit actin filaments, which form bundles around the microtubules at concentrations insufficient for microtubule-independent actin bundle formation. When the microtubules depolymerize the actin bundles prevail at the positions and orientations predetermined by the microtubules. This readily suggests a mechanism explaining how exploratory microtubules in filo- and lamellipodia set the positions of actin bundles, for example in neuronal growth cones.

Stargardt-like Clinical Characteristics and Disease Course Associated with Variants in the WDR19 Gene.

Variants in WDR19 (IFT144) have been implicated as another possible cause of Stargardt disease. The purpose of this study was to compare longitudinal multimodal imaging of a WDR19-Stargardt patient, harboring p.(Ser485Ile) and a novel c.(3183+1_3184-1)_(3261+1_3262-1)del variant, with 43 ABCA4-Stargardt patients. Age at onset, visual acuity, Ishihara color vision, color fundus, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (OCT) images, microperimetry and electroretinography (ERG) were evaluated. First symptom of WDR19 patient was nyctalopia at the age of 5 years. After the age of 18 years, OCT showed hyper-reflectivity at the level of the external limiting membrane/outer nuclear layer. There was abnormal cone and rod photoreceptor function on ERG. Widespread fundus flecks appeared, followed by perifoveal photoreceptor atrophy. Fovea and peripapillary retina remained preserved until the latest exam at 25 years of age. ABCA4 patients had median age of onset at 16 (range 5-60) years and mostly displayed typical Stargardt triad. A total of 19% had foveal sparing. In comparison to ABCA4 patients, the WDR19 patient had a relatively large foveal preservation and severe rod photoreceptor impairment; however, it was still within the ABCA4 disease spectrum. Addition of WDR19 in the group of genes producing phenocopies of Stargardt disease underlines the importance of genetic testing and may help to understand its pathogenesis.

Cone Structure and Function in RPGR- and USH2A-Associated Retinal Degeneration

To compare cone structure and function between RPGR- and USH2A-associated retinal degeneration. Retrospective, observational, cross-sectional study. This multicenter study included 13 eyes (9 participants) with RPGR-related X-linked retinitis pigmentosa (RPGR), 15 eyes (10 participants) with USH2A-related Usher syndrome type 2 (USH2), 16 eyes (9 participants) with USH2A-related autosomal recessive retinitis pigmentosa (ARRP), and 7 normal eyes (6 participants). Structural measures included cone spacing and density from adaptive optics scanning laser ophthalmoscopy and photoreceptor inner segment (IS), outer segment (OS), and outer nuclear layer (ONL) thickness from optical coherence tomography (OCT) images. OCT angiography images were used to study choriocapillaris flow deficit percent (CCFD). Cone function was assessed by fundus-guided microperimetry. Measures were compared at designated regions using analysis of variance with pairwise comparisons among disease groups, adjusted for disease duration and eccentricity. OCT segmentation revealed shorter OS and IS, with reduced ONL thickness in RPGR compared to normal (OS: P < .001, IS: P=.001, ONL: P=.005), USH2 (OS: P=.01, IS: P=.03, ONL: P=.03), or ARRP (OS: P=.001, ONL: P=.03). Increased cone spacing was observed in both RPGR (P=.03) and USH2 compared with normal (P=.048). The mean CCFD in RPGR was greater than in USH2 (P=.02). Microperimetry demonstrated below-normal regional sensitivity in RPGR (P=.004), USH2 (P=.02), and ARRP (P=.009), without significant intergroup differences. Outer retinal structure and choriocapillaris perfusion were more abnormal in RPGR- than USH2A-related retinal degenerations, whereas there were no significant differences in below-normal regional sensitivity between each rod-cone degeneration associated with variants in these 2 genes expressed at the photoreceptor-connecting cilium.

An Alternative Way to Mapping Cone: The Algebraic Topology of the Pinched Tensor

An Alternative Way to Mapping Cone: The Algebraic Topology of the Pinched Tensor