Mutations in the gene encoding rhodopsin, the visual pigment in rod photoreceptors, lead to retinal degeneration in species from Drosophila to man. The pathogenic sequence from rod cell-specific mutation to degeneration of rods and cones remains unclear. To understand the disease process in man, we studied heterozygotes with 18 different rhodopsin gene mutations by using noninvasive tests of rod and cone function and retinal histopathology. Two classes of disease expression were found, and there was allele-specificity. Class A mutants lead to severely abnormal rod function across the retina early in life; topography of residual cone function parallels cone cell density. Class B mutants are compatible with normal rods in adult life in some retinal regions or throughout the retina, and there is a slow stereotypical disease sequence. Disease manifests as a loss of rod photoreceptor outer segments, not singly but in microscopic patches that coalesce into larger irregular areas of degeneration. Cone outer segment function remains normal until >75% of rod outer segments are lost. The topography of cone loss coincides with that of rod loss. Most class B mutants show an inferior-nasal to superior-temporal retinal gradient of disease vulnerability associated with visual cycle abnormalities. Class A mutant alleles behave as if cytotoxic; class B mutants can be relatively innocuous and epigenetic factors may play a major role in the retinal degeneration.
Purpose To describe the prevalence and interrelationships of epiretinal membranes, vitreomacular traction, macular cysts, paravascular cysts, lamellar macular holes, full-thickness macular holes, and visual impairment in a population-based study of older adults. Design Cross-sectional study. Participants There were 1913 participants aged 63–102 years at the 20-year Beaver Dam Eye Study follow-up examination in 2008–2010, of whom 1540 (2980 eyes) had gradable spectral-domain optical coherence tomography (SD-OCT) scans of the macula in at least one eye. Methods The presence of epiretinal membranes and other retinal lesions was determined by standardized grading of macular SD-OCT scans and photographs of three standard fields. Main Outcome Measures Epiretinal membranes, vitreomacular traction, macular cysts, paravascular cysts, lamellar macular holes, full-thickness macular holes, and visual impairment. Results Using SD-OCT the prevalences of epiretinal membranes (34.1%), vitreomacular traction (1.6%), macular cysts (5.7%), paravascular cysts (20.0%), lamellar macular holes (3.6%), and full-thickness macular holes (0.4%) were estimated. The prevalences of macular cysts (P<0.001), epiretinal membranes (P<0.001), and vitreomacular traction (P=0.005) increased with age, the prevalence of paravascular cysts (P=0.05) decreased with age, and the prevalence of lamellar macular holes was not associated with age (P=0.70). The prevalences of macular cysts, lamellar macular holes, and epiretinal membranes were higher in eyes with a history of cataract surgery. Macular cysts and epiretinal membranes were more common in eyes with retinal diseases such as proliferative diabetic retinopathy, retinal vein occlusion, and retinal detachment than in eyes without these conditions. Macular cysts, epiretinal membranes, and full-thickness macular holes were associated with visual impairment. While adjusting for age and sex, macular cysts (odds ratio [OR] 3.96; P<0.0001), paravascular cysts (OR 1.45, P=0.007), lamellar macular holes (OR 10.62; P<0.001), vitreomacular traction (OR 2.72, P=0.01) and visual impairment (OR 3.23; p<0.001) were more frequent in eyes with epiretinal membranes compared to eyes without. Conclusions Epiretinal membranes are associated with macular cysts, paravascular cysts, lamellar macular holes, vitreomacular traction, and visual impairment. Further follow-up will allow better understanding of the natural history of epiretinal membranes and vitreomacular traction and their relationships to the development of macular cysts and lamellar macular holes in the aging population.
Recombinant adeno-associated virus (rAAV) is a promising vector for therapy of retinal degenerative diseases. We evaluated the efficiency, cellular specificity, and safety of retinal cell transduction in nonhuman primates after subretinal delivery of an rAAV carrying a cDNA encoding green fluorescent protein (EGFP), rAAV.CMV.EGFP. The treatment results in efficient and stable EGFP expression lasting >1 year. Transgene expression in the neural retina is limited exclusively to rod photoreceptors. There is neither electroretinographic nor histologic evidence of photoreceptor toxicity. Despite significant serum antibody responses to the vector, subretinal readministration results in additional transduction events. The findings further characterize the retinal cell tropism of rAAV. They also support the development of studies aimed ultimately at treating inherited retinal degeneration by using rAAV-mediated gene therapy.
Time delay estimation (TDE) is commonly performed in practice by crosscorrelation of digitized echo signals. Since time delays are generally not integral multiples of the sampling period, the location of the largest sample of the crosscorrelation function (ccf) is an inexact estimator of the location of the peak. Therefore, one must interpolate between the samples of the ccf to improve the estimation precision. Using theory and simulations, we review and compare the performance of several methods for interpolation of the ccf. The maximum likelihood approach to interpolation is the application of a reconstruction filter to the discrete ccf. However, this method can only be approximated in practice and can be computationally intensive. For these reasons, a simple method is widely used that involves fitting a parabola (or other curve) to samples of the ccf in the neighborhood of its peak. We describe and compare two curve-fitting methods: parabolic and cosine interpolation. Curve-fitting interpolation can yield biased time-delay estimates, which may preclude the use of these methods in some applications. The artifactual effect of these bias errors on elasticity imaging by elastography is discussed. We demonstrate that reconstructive interpolation is unbiased. An iterative implementation of the reconstruction procedure is proposed that can reduce the computation time significantly.
The use of carbon-dot-based dual-emission fluorescent nanohybrids (DEFNs) as versatile nanothermometry devices for spatially resolved temperature measurements in living cells is demonstrated. The carbon dots (CDs) are prepared in the organic phase and display tunable photoluminescence (PL) across a wide visible range by adjusting the excitation wavelengths and extend of N-doping. DEFNs are formed in a straightforward fashion from CDs (emitting blue PL) and gold nanoclusters (AuNCs, emitting red PL). The DEFNs display ideal single-excitation, dual-emission with two well-resolved, intensity-comparable fluorescence peaks, and function in optical thermometry with high reliability and accuracy by exploiting the temperature sensitivity of their fluorescence intensity ratio (blue/red). Furthermore, the DEFNs have been introduced into cells, exhibiting good biocompatibility, and have facilitated physiological temperature measurements in the range of 25-45 °C; the DEFNs can therefore function as "non-contact" tools for the accurate measurement of temperature and its gradient inside a living cell.
Although the synthesis of two-dimensional (2D) layered MoS2 nanomaterials have been developing rapidly, there are many technical issues in preparing MoS2 quantum dots (QDs) with photoluminescence property. Herein, we design a facile colloidal chemical route to prepare photoluminescent MoS2 QDs using the ammonium tetrathiomolybdate ((NH4)2MoS4) as precursors and oleyl amine as reducing agent. The optical property and structure of as-prepared MoS2 QDs are investigated systematically. Resultant MoS2 QDs exhibit fluorescence (λmax=575 nm; quantum yield, 4.4%), spherical morphology with uniform thickness of ~3 nm and excitation-dependent PL phenomenon. Moreover, resultant MoS2 QDs show size-dependent tunable photoluminescence in wide visible region. With the help of the amphiphilic compound, resultant MoS2 QDs could be transferred from organic to aqueous phase. MoS2 QDs in aqueous solution have many advantages, such as good dispersion, low toxicity and photoluminescent property which make them possess promising applications in optoelectronic and biological fields. In this study, the 293T cells are used as a model to evaluate the fluorescence imaging of MoS2 QDs. The results confirm fluorescent signal appears in cytoplasm which demonstrates asprepared MoS2 QDs could be used as a probe for real-time optical cellular imaging.
Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general.
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