Rod Function Research Articles

ЗАСТОСУВАННЯ МЕТОДУ ГРАНИЧНИХ ЕЛЕМЕНТІВ ДЛЯ РОЗРАХУНКУ НАПРУЖЕНО-ДЕФОРМОВАНОГО СТАНУ ПРИ КРУЧЕННІ ТОНКОСТІННИХ РАМ АВТОМОБІЛІВ

Currently, the main method of calculating the stress-strain state (SSS) is the finite element method (FEM), implemented in software packages such as ANSYS, Solid Works, MATLAB, and others. It is established that if the SSS structure is described by rod functions, then the finite element method gives accurate results. If the state of the object is described by other functions, then MSE can give only approximate results of SSS calculation. Therefore, in this work, the authors applied a more accurate method of calculating the SSS of thin-walled car frames – the numerical analytical method of boundary elements (NA BEM). The purpose of the study is to apply a more accurate method of calculating the SSS of thin-walled car frames with the help of BEM. The scientific and practical direction of the work is that the technology of a more accurate method of calculating the SSS of thin-walled car frames - NA BEM is applied. The research methodology is the construction of mathematical models for the calculation of thin-walled car frames – NA BEM. When designing thin-walled metal structures, SSS is described by hyperbolic functions, and FEM, in principle, cannot provide accurate results for calculating SSS of thin-walled structures. Therefore, in the work, it is proposed to apply the technology of the boundary element method, which is free from the shortcomings of FEM technologies, to calculate SSS torsion of thin-walled car frames. The paper presents the matrix functions of the solution of the differential equations of the finite torsion of thin-walled frames, which were used to calculate the SSS of the rod torsion of thin-walled car frames. A more accurate SSS calculation of thin-walled car frames has been performed. This, in turn, will make it possible to determine the exact dimensions of the cross-section of thin-walled car frames. The result of the conducted research is the construction of accurate models of the stress-strain state during torsion of thin-walled car frames. Systems of linear equations of the SSS calculation algebra of limited torsion of two inseparable beams, which are models of car frames, are given. The calculation of frames for compressed torsion is presented. Отримані точні результати розрахунку SSS обмеженого кручення рам автомобілів, що представлені у вигляді таблиць і епюр. Keywords: FEM, BEM, thin-walled car frames.

Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness

Congenital stationary night blindness (CSNB) is a group of inherited retinal diseases in which either rod-to-ON-bipolar cell (ON-BC) signaling, or rod function is affected leading to impaired vision under low light conditions. One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips. We have previously characterized a canine model of LRIT3-CSNB and demonstrated short-term safety and efficacy of an ON-BC targeting AAV-LRIT3 (AAVK9#4-shGRM6-cLRIT3-WPRE) gene therapy. Herein, we demonstrate long-term functional recovery and molecular restoration following subretinal injection of the ON-BC targeting AAV-LRIT3 vector in all eight treated eyes for up to 32 months. Following subretinal administration of the therapeutic vector, expression of the LRIT3 transgene, as well as restoration of mGluR6 signaling cascade member TRPM1, were confirmed in the outer plexiform layer (OPL) of the treated area. However, further investigation of the transgene LRIT3 transcript expression by RNA in situ hybridization (RNA-ISH) revealed off-target expression in non-BCs including the photoreceptors, inner nuclear, and ganglion cell layers, despite the use of a mutant AAVK9#4 capsid and an improved mGluR6 promoter designed to specifically transduce and promote expression in ON-BCs. While the long-term therapeutic potential of AAVK9#4-shGRM6-cLRIT3-WPRE is promising, we highlight the necessity for further optimization of AAV-LRIT3 therapy in the canine CSNB model prior to its clinical application.

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.

Transient Receptor Potential channels (TRP) in GtoPdb v.2023.1

Transient Receptor Potential channels (TRP) in GtoPdb v.2023.1

Improved Rod Sensitivity as Assessed by Two-Color Dark-Adapted Perimetry in Patients With RPE65-Related Retinopathy Treated With Voretigene Neparvovec-rzyl.

The purpose of this study was to evaluate rod-mediated function with two-color dark-adapted perimetry (2cDAP) in patients with RPE65-related retinopathy treated with voretigene neparvovec-rzyl. Following dilation and dark adaptation, 2cDAP and FST were performed. The 2cDAP was measured on an Octopus 900 perimeter (Haag-Streit) with cyan (500 nm wavelength) and red (650 nm wavelength) stimuli. Hill of vision (HOV) analysis was performed on 2cDAP perimetry with Visual Field Modeling and Analysis (VFMA). Full field threshold stimulus testing (FST) was also measured as a secondary measure of rod-mediated function, and assessed on a Diagnosys Espion with the ColorDome stimulator (Diagnosys LLC). Eight eyes from 4 patients who were treated with voretigene bilaterally had rod function assessed by 2cDAP testing at least 1 year after treatment. There was statistically significant improvement in 2cDAP following gene augmentation therapy. HOV VFMA analysis showed widespread improvements that extended beyond the treatment bleb and statistically significant improvement in HOV analysis volumetric measurements post-treatment to cyan and red stimuli. FST testing performed in six eyes from three patients demonstrated statistically significant improvement to all chromatic stimuli following treatment. These findings demonstrated statistically significant improvement in 2cDAP and FST following treatment with voretigene. These findings provide a sensitive method of assessing rod-mediated function in a topographic manner that may be useful in future clinical trials for inherited retinal dystrophies.

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.

Roma Dönemi Cam Çubuklarının Kozmetik Alanda Kullanımı Üzerine: Arkeolojik Veriler Işığında Genel Anlayışa Alternatif Yaklaşımlar

During the Roman period, the production and use of glass rods were widespread. Numerous archaeological contexts and examples have been discovered in museums and private collections. The majority of these works, which were created utilizing the free-shaping technique, are composed of light blue and green glass. The literature emphasizes the use of glass rods as stirring and spatula rods, particularly in the cosmetics industry. This widespread understanding has led to the evaluation of glass rods, which have similar forms but different uses and functions, in the field of cosmetic products. Thus, artifacts whose utilization area and structural functions could not be completely specified were characterized and categorized in a simple manner, typically by evaluating them within the realm of cosmetic aesthetics. In this regard, our study indicates that glass rods are utilized in fields such as accessories, writing instruments, architecture, and textiles, in addition to the field of cosmetics, and it has been demonstrated that the rods serve a variety of purposes. For this purpose, attention was drawn to the necessity of determining the usage area and function of glass rods and reviewing the definition and classification features of similar artifacts in museums.

Investigating the Role of Rhodopsin F45L Mutation in Mouse Rod Photoreceptor Signaling and Survival.

Rhodopsin is the critical receptor molecule which enables vertebrate rod photoreceptor cells to detect a single photon of light and initiate a cascade of molecular events leading to visual perception. Recently, it has been suggested that the F45L mutation in the transmembrane helix of rhodopsin disrupts its dimerization in vitro To determine whether this mutation of rhodopsin affects its signaling properties in vivo, we generated knock-in mice expressing the rhodopsin F45L mutant. We then examined the function of rods in the mutant mice versus wild-type controls, using in vivo electroretinography and transretinal and single cell suction recordings, combined with morphologic analysis and spectrophotometry. Although we did not evaluate the effect of the F45L mutation on the state of dimerization of the rhodopsin in vivo, our results revealed that F45L-mutant mice exhibit normal retinal morphology, normal rod responses as measured both in vivo and ex vivo, and normal rod dark adaptation. We conclude that the F45L mutation does not affect the signaling properties of rhodopsin in its natural setting.

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.

Rod photoreceptor activation and deactivation in early-stage diabetic eye disease.

To infer rod phototransduction activation and deactivation characteristics in diabetics who have mild or no clinically-apparent retinopathy. Fifteen non-diabetic controls, 15 diabetics with no clinically-apparent diabetic retinopathy (NDR), and 15 diabetics with mild non-proliferative diabetic retinopathy (MDR) participated. Dark-adapted flash electroretinograms (3.2 to 4.4 log scot td-s) were recorded to assess rod activation. The a-waves were fit with a Gaussian model to derive Rmp3 (maximum photoreceptor response amplitude) and S (phototransduction sensitivity). Rod deactivation was assessed with a paired flash paradigm, in which a-waves were measured for two flashes separated by inter-stimulus intervals (ISIs) of 0.125 to 16s. The ISI needed for the a-wave amplitude of the second flash to recover to 50% of the first flash (t50) was determined. The effect of stimulus retinal illuminance on activation and deactivation was evaluated in a subset of control subjects. Analysis of variance indicated that both diabetic groups had significant log S reductions compared to controls (p < 0.001). Mean S was reduced by approximately 49% and 78% for the NDR and MDR groups, respectively. In contrast, log Rmp3 and log t50 did not differ significantly among the groups (both p > 0.08). Reducing stimulus retinal illuminance significantly reduced S, but did not significantly affect Rmax or t50. Only phototransduction sensitivity was abnormal in this sample of diabetic subjects. The normal deactivation kinetics suggests that circulating rod current is normal. These findings begin to constrain possible explanations for abnormal rod function in early diabetic retinal disease.

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.

A mouse model of cone photoreceptor function loss (cpfl9) with degeneration due to a mutation in Gucy2e.

During routine screening of mouse strains and stocks by the Eye Mutant Resource at The Jackson Laboratory for genetic mouse models of human ocular disorders, we identified cpfl9, a mouse model with cone photoreceptor function loss. The mice exhibited an early-onset phenotype that was easily recognized by the absence of a cone-mediated b-wave electroretinography response and by a reduction in rod-mediated photoresponses at four weeks of age. By genetic mapping and high-throughput sequencing of a whole exome capture library of cpfl9, a homozygous 25 bp deletion within exon 11 of the Gucy2e gene was identified, which is predicted to result in a frame shift leading to premature termination. The corresponding protein in human, retinal guanylate cyclase 1 (GUCY2D), plays an important role in rod and cone photoreceptor cell function. Loss-of-function mutations in human GUCY2D cause LCA1, one of the most common forms of Leber congenital amaurosis, which results in blindness at birth or in early childhood. The early loss of cone and reduced rod photoreceptor cell function in the cpfl9 mutant is accompanied by a later, progressive loss of cone and rod photoreceptor cells, which may be relevant to understanding disease pathology in a subset of LCA1 patients and in individuals with cone-rod dystrophy caused by recessive GUCY2D variants. cpfl9 mice will be useful for studying the role of Gucy2e in the retina.

Custom software development of structural dimension optimization software for the buckling of stiffened plates

&lt;abstract&gt; &lt;p&gt;Existing structural optimization software tools only integrate the Euler buckling function of rods and plates and do not consider the buckling strength constraint of stiffened plates, thus failing to meet the optimization design requirements of thin-walled structures such as ship hulls. In this study, according to the buckling strength specifications for stiffened plates of ships, the custom software development of a structural optimization program with "buckling constraints of stiffened plates" was performed using the HyperMesh optimization design software. The finite-element grid of the stiffened plate was divided; the average stress, stress gradient and other parameters associated with the buckling of stiffened plates were determined; the DRESP3 card was set; the external OML function file was linked and the buckling strength of the stiffened plates was introduced into the dimensional optimization design model as a constraint. The proposed method was used to optimize the structure scantlings of a platform, achieving a reduction of 8.96% compared with the original scheme, while also meeting the requirements of structural strength, deformation and buckling strength. The results demonstrated that the dimensional optimization software with buckling constraints is operable and can aid in the rapid structural optimization design of stiffened plates.&lt;/p&gt; &lt;/abstract&gt;

Medications Damaging Retinal Pigment Epithelium and Photoreceptor Complex-3: Pathogenesis, Diagnosis and Treatment (Clofazimine, Deferoxamine, Vitamin A Deficiency and Celiac Disease, Digoxin)

Toxic retinopathies are a variety of conditions resulting from retinal damage caused by systemically administered drugs. Although relatively rare, these conditions should be considered, especially when features of unusual retinopathy or maculopathy such as bilateral pigmentary disorder or retinal crystal deposition are present. It has been observed that some drugs damage the RPE and photoreceptor layer. Of these drugs, clofazimine; can be used in the treatment of tuberculosis, leprosy, and various cutaneous diseases, but it can cause color vision defects and bulls-eye maculopathy in a dose-dependent manner. Lesions detectable by various imaging methods have been described as associated with the use of deferoxamine mesylate, which is used as an iron-chelating agent. In vitamin A deficiency characterized by xerophthalmia symptoms, drusenoid deposits have been observed in the photoreceptor outer segment, in which rod function defects are prominent. In the use of digoxin, which has a very narrow therapeutic range, photoreceptor dysfunctions, which are manifested by deterioration in color perception, may develop. Most ocular side effects associated with systemic drug use are reversible after discontinuation of therapy if detected early. However, toxic effects can progress if undetected and cause retinal dysfunction associated with potentially irreversible vision loss.

Photoreceptor Function and Structure in Autosomal Dominant Vitelliform Macular Dystrophy Caused by BEST1 Mutations.

The purpose of this study was to evaluate rod and cone function and outer retinal structure within macular lesions, and surrounding extralesional areas of patients with autosomal dominant Best vitelliform macular dystrophy caused by BEST1 mutations. Seventeen patients from seven families were examined with dark- and light-adapted chromatic perimetry and optical coherence tomography. Subsets of patients had long-term follow-up (14-22 years, n = 6) and dark-adaptation kinetics measured (n = 5). Within central lesions with large serous retinal detachments, rod sensitivity was severely reduced but visual acuity and cone sensitivity were relatively retained. In surrounding extralesional areas, there was a mild but detectable widening of the subretinal space in some patients and some retinal areas. Available evidence was consistent with subretinal widening causing slower dark-adaptation kinetics. Over long-term follow-up, some eyes showed formation of de novo satellite lesions at retinal locations that years previously demonstrated subretinal widening. A subclinical abnormality consisting of a retina-wide mild thickening of the outer nuclear layer was evident in many patients and thickening increased in the subset of patients with long-term follow-up. Outcome measures for future clinical trials should include evaluations of rod sensitivity within central lesions and quantitative measures of outer retinal structure in normal-appearing regions surrounding the lesions.

Use of the Medmont Dark-Adapted Chromatic Perimeter for Assessing Rod Function in Retinitis Pigmentosa.

Medmont Dark-Adapted Chromatic (DAC) Perimeter enables efficient and quantifiable evaluation of rod-mediated (scotopic) vision. DAC tests rod function at multiple retinal locations, creating a topographical map of rod-mediated vision. These dynamic rod responses can be used as a functional marker to monitor disease progression and functional alterations in inherited retinal dystrophies, such as retinitis pigmentosa, Stargardt disease, cone-rod dystrophy, and choroideremia. In this chapter, we describe a protocol for the operation and analysis of the Medmont DAC in monitoring and assessing various retinal disorders.

Two-Color Dark-Adapted Perimetry Implemented With a Commercially Available Perimeter to Characterize Rod-Pathway Sensitivity.

To characterize rod-pathway function across the visual field using 2-color dark-adapted perimetry (2cDAP) implemented with conventional Octopus 900 Pro perimeters. Eighteen visually normal individuals and two retinitis pigmentosa (RP) patients participated. Thresholds were measured under dark-adapted conditions at 15 locations along the horizontal meridian using short (450 nm) and long (610 nm) wavelength stimuli. Threshold differences between the two wavelengths were used to determine rod- vs cone-mediated function. Among controls, peripheral and perifoveal thresholds for the short-wavelength stimulus were approximately 2 log units lower than for the long-wavelength stimulus. Foveal thresholds for the two wavelengths were similar. RP threshold profiles differed considerably from the controls, with normal foveal thresholds and high peripheral thresholds for both wavelengths. 2cDAP can be performed with an unmodified Octopus perimeter to evaluate rod function across the visual field and obtain information that is not available with standard automated perimetry. [Ophthalmic Surg Lasers Imaging Retina 2022;53:692-696.].

Photoreceptor function and structure in retinal degenerations caused by biallelic BEST1 mutations

The only approved retinal gene therapy is for biallelic RPE65 mutations which cause a recessive retinopathy with a primary molecular defect located at the retinal pigment epithelium (RPE). For a distinct recessive RPE disease caused by biallelic BEST1 mutations, a pre-clinical proof-of-concept for gene therapy has been demonstrated in canine eyes. The current study was undertaken to consider potential outcome measures for a BEST1 clinical trial in patients demonstrating a classic autosomal recessive bestrophinopathy (ARB) phenotype. Spatial distribution of retinal structure showed a wide expanse of abnormalities including large intraretinal cysts, shallow serous retinal detachments, abnormalities of inner and outer segments, and an unusual prominence of the external limiting membrane. Surrounding the central macula extending from 7 to 30 deg eccentricity, outer nuclear layer was thicker than expected from a cone only retina and implied survival of many rod photoreceptors. Co-localized however, were large losses of rod sensitivity despite preserved cone sensitivities. The dissociation of rod function from rod structure observed, supports a large treatment potential in the paramacular region for biallelic bestrophinopathies.

CGMP Analogues with Opposing Actions on CNG Channels Selectively Modulate Rod or Cone Photoreceptor Function.

The vertebrate retina harbors rod and cone photoreceptors. Human vision critically depends on cone photoreceptor function. In the phototransduction cascade, cGMP activates distinct rod and cone isoforms of the cyclic nucleotide-gated (CNG) channel. Excessive cGMP levels initiate a pathophysiological rollercoaster, which starts with CNG channel over-activation, typically in rod photoreceptors. This triggers cell death of rods first, and then cones, and is the root cause of many blinding retinal diseases, including Retinitis pigmentosa. While targeting of CNG channels has been proposed for therapeutic purposes, thus far, it has not been possible to inhibit rod CNG channels without compromising cone function. Here, we present a novel strategy, based on cGMP analogues with opposing actions on CNG channels, which enables the selective modulation of either rod or cone photoreceptor activity. The combined treatment with the weak rod-selective CNG-channel inhibitor (Rp-8-Br-PET-cGMPS) and the cone-selective CNG-channel activator (8-pCPT-cGMP) essentially normalized rod CNG-channel function while preserving cone functionality at physiological and pathological cGMP levels. Hence, combinations of cGMP analogues with desired properties may elegantly address the isoform-specificity problem in future pharmacological therapies. Moreover, this strategy may allow for improvements in visual performance in certain light environments.

Residual rod function in CNGB1 mutant dogs.

Mutations in the cyclic nucleotide-gated (CNG) channel beta subunit (CNGB1) are an important cause of recessive retinitis pigmentosa. We identified a large animal model with a truncating mutation of CNGB1. This study reports the persistence of small, desensitized rod ERG responses in this model. Dark-, light-adapted and chromatic ERGs were recorded in CNGB1 mutant dogs and age and breed matched controls. Comparisons were made with a dog model known to completely lack rod function; young dogs with a mutation in the rod phosphodiesterase 6 alpha subunit (PDE6A-/-). Immunohistochemistry (IHC) to label the rod CNG alpha (CNGA1) and CNGB1 subunits was performed. The dark-adapted ERG of CNGB1 mutant dogs had a raised response threshold with lack of normal rod response and a remaining cone response. Increasing stimulus strength resulted in the appearance of a separate, slower positive waveform following the dark-adapted cone b-wave. With increasing stimulus strength this increased in amplitude and became faster to merge with the initial b-wave. Comparison of responses from PDE6A-/- (cone only dogs) with CNGB1 mutant dogs to red and blue flashes and between dark-adapted and light-adapted responses supported the hypothesis that the CNGB1 mutant dog had residual desensitized rod responses. CNGB1 mutant dogs had a small amount of CNGA1 detectable in the outer segments. CNGB1 mutant dogs have a residual ERG response from desensitized rods. This may be due to low levels of CNGA1 in outer segments.