Cone Photoreceptor Structure in Patients With X-Linked Cone Dysfunction and Red-Green Color Vision Deficiency

PubMed Central

Patterson, Emily J.; Wilk, Melissa; Langlo, Christopher S.; Kasilian, Melissa; Ring, Michael; Hufnagel, Robert B.; Dubis, Adam M.; Tee, James J.; Kalitzeos, Angelos; Gardner, Jessica C.; Ahmed, Zubair M.; Sisk, Robert A.; Larsen, Michael; Sjoberg, Stacy; Connor, Thomas B.; Dubra, Alfredo; Neitz, Jay; Hardcastle, Alison J.; Neitz, Maureen; Michaelides, Michel; Carroll, Joseph

2016-01-01

Purpose Mutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/M opsin gene mutations to clarify the link between color vision deficiency and cone dysfunction. Methods We recruited 17 males for imaging. The thickness and integrity of the photoreceptor layers were evaluated using spectral-domain optical coherence tomography. Cone density was measured using high-resolution images of the cone mosaic obtained with adaptive optics scanning light ophthalmoscopy. The L/M opsin gene array was characterized in 16 subjects, including at least one subject from each family. Results There were six subjects with the LVAVA haplotype encoded by exon 3, seven with LIAVA, two with the Cys203Arg mutation encoded by exon 4, and two with a novel insertion in exon 2. Foveal cone structure and retinal thickness was disrupted to a variable degree, even among related individuals with the same L/M array. Conclusions Our findings provide a direct link between disruption of the cone mosaic and L/M opsin variants. We hypothesize that, in addition to large phenotypic differences between different L/M opsin variants, the ratio of expression of first versus downstream genes in the L/M array contributes to phenotypic diversity. While the L/M opsin mutations underlie the cone dysfunction in all of the subjects tested, the color vision defect can be caused either by the same mutation or a gene rearrangement at the same locus. PMID:27447086

Identification of a cone bipolar cell in cat retina which has input from both rod and cone photoreceptors.

PubMed

Fyk-Kolodziej, Bozena; Qin, Pu; Pourcho, Roberta G

2003-09-08

It has been generally accepted that rod photoreceptor cells in the mammalian retina make synaptic contact with only a single population of rod bipolar cells, whereas cone photoreceptors contact a variety of cone bipolar cells. This assumption has been challenged in rodents by reports of a type of cone bipolar cell which receives input from both rods and cones. Questions remained as to whether similar pathways are present in other mammals. We have used an antiserum against the glutamate transporter GLT1-B to visualize a population of cone bipolar cells in the cat retina which make flat contacts with axon terminals of both rod and cone photoreceptor cells. These cells are identified as OFF-cone bipolar cells and correspond morphologically to type cb1 (CBa2) cone bipolar cells which are a major source of input to OFF-beta ganglion cells in the cat retina. The GLT1-B transporter was also localized to processes making flat contacts with photoreceptor terminals in rat and rabbit retinas. Examination of tissue processed for the GluR1 glutamate receptor subunit showed that cb1 cone bipolar cells, like their rodent counterparts, express this alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-selective receptor at their contacts with rod spherules. Thus, a direct excitatory pathway from rod photoreceptors to OFF-cone bipolar cells appears to be a common feature of mammalian retinas. Copyright 2003 Wiley-Liss, Inc.

Multiple rod-cone and cone-rod photoreceptor transmutations in snakes: evidence from visual opsin gene expression.

PubMed

Simões, Bruno F; Sampaio, Filipa L; Loew, Ellis R; Sanders, Kate L; Fisher, Robert N; Hart, Nathan S; Hunt, David M; Partridge, Julian C; Gower, David J

2016-01-27

In 1934, Gordon Walls forwarded his radical theory of retinal photoreceptor 'transmutation'. This proposed that rods and cones used for scotopic and photopic vision, respectively, were not fixed but could evolve into each other via a series of morphologically distinguishable intermediates. Walls' prime evidence came from series of diurnal and nocturnal geckos and snakes that appeared to have pure-cone or pure-rod retinas (in forms that Walls believed evolved from ancestors with the reverse complement) or which possessed intermediate photoreceptor cells. Walls was limited in testing his theory because the precise identity of visual pigments present in photoreceptors was then unknown. Subsequent molecular research has hitherto neglected this topic but presents new opportunities. We identify three visual opsin genes, rh1, sws1 and lws, in retinal mRNA of an ecologically and taxonomically diverse sample of snakes central to Walls' theory. We conclude that photoreceptors with superficially rod- or cone-like morphology are not limited to containing scotopic or photopic opsins, respectively. Walls' theory is essentially correct, and more research is needed to identify the patterns, processes and functional implications of transmutation. Future research will help to clarify the fundamental properties and physiology of photoreceptors adapted to function in different light levels. © 2016 The Author(s).

Rod-cone interaction in light adaptation

PubMed Central

Latch, M.; Lennie, P.

1977-01-01

1. The increment-threshold for a small test spot in the peripheral visual field was measured against backgrounds that were red or blue. 2. When the background was a large uniform field, threshold over most of the scotopic range depended exactly upon the background's effect upon rods. This confirms Flamant & Stiles (1948). But when the background was small, threshold was elevated more by a long wave-length than a short wave-length background equated for its effect on rods. 3. The influence of cones was explored in a further experiment. The scotopic increment-threshold was established for a short wave-length test spot on a large, short wave-length background. Then a steady red circular patch, conspicuous to cones, but below the increment-threshold for rod vision, was added to the background. When it was small, but not when it was large, this patch substantially raised the threshold for the test. 4. When a similar experiment was made using, instead of a red patch, a short wave-length one that was conspicuous in rod vision, threshold varied similarly with patch size. These results support the notion that the influence of small backgrounds arises in some size-selective mechanism that is indifferent to the receptor system in which visual signals originate. Two corollaries of this hypothesis were tested in further experiments. 5. A small patch was chosen so as to lift scotopic threshold substantially above its level on a uniform field. This threshold elevation persisted for minutes after extinction of the patch, but only when the patch was small. A large patch made bright enough to elevate threshold by as much as the small one gave rise to no corresponding after-effect. 6. Increment-thresholds for a small red test spot, detected through cones, followed the same course whether a large uniform background was long- or short wave-length. When the background was small, threshold upon the short wave-length one began to rise for much lower levels of background illumination

Correlated cone noise decreases rod signal contributions to the post-receptoral pathways.

PubMed

Hathibelagal, Amithavikram R; Feigl, Beatrix; Zele, Andrew J

2018-04-01

This study investigated how invisible extrinsic temporal white noise that correlates with the activity of one of the three [magnocellular (MC), parvocellular (PC), or koniocellular (KC)] post-receptoral pathways alters mesopic rod signaling. A four-primary photostimulator provided independent control of the rod and three cone photoreceptor excitations. The rod contributions to the three post-receptoral pathways were estimated by perceptually matching a 20% contrast rod pulse by independently varying the LMS (MC pathway), +L-M (PC pathway), and S-cone (KC pathway) excitations. We show that extrinsic cone noise caused a predominant decrease in the overall magnitude and ratio of the rod contributions to each pathway. Thus, the relative cone activity in the post-receptoral pathways determines the relative mesopic rod inputs to each pathway.

Deletion of the X-linked opsin gene array locus control region (LCR) results in disruption of the cone mosaic.

PubMed

Carroll, Joseph; Rossi, Ethan A; Porter, Jason; Neitz, Jay; Roorda, Austin; Williams, David R; Neitz, Maureen

2010-09-15

Blue cone monochromacy (BCM) is an X-linked condition in which long- (L) and middle- (M) wavelength-sensitive cone function is absent. Due to the X-linked nature of the condition, female carriers are spared from a full manifestation of the associated defects but can show visual symptoms, including abnormal cone electroretinograms. Here we imaged the cone mosaic in four females carrying an L/M array with deletion of the locus control region, resulting in an absence of L/M opsin gene expression (effectively acting as a cone opsin knockout). On average, they had cone mosaics with reduced density and disrupted organization compared to normal trichromats. This suggests that the absence of opsin in a subset of cones results in their early degeneration, with X-inactivation the likely mechanism underlying phenotypic variability in BCM carriers. Copyright 2010 Elsevier Ltd. All rights reserved.

Weak endogenous Ca2+ buffering supports sustained synaptic transmission by distinct mechanisms in rod and cone photoreceptors in salamander retina

PubMed Central

Van Hook, Matthew J; Thoreson, Wallace B

2015-01-01

Differences in synaptic transmission between rod and cone photoreceptors contribute to different response kinetics in rod- versus cone-dominated visual pathways. We examined Ca2+ dynamics in synaptic terminals of tiger salamander photoreceptors under conditions that mimicked endogenous buffering to determine the influence on kinetically and mechanistically distinct components of synaptic transmission. Measurements of ICl(Ca) confirmed that endogenous Ca2+ buffering is equivalent to ˜0.05 mmol/L EGTA in rod and cone terminals. Confocal imaging showed that with such buffering, depolarization stimulated large, spatially unconstrained [Ca2+] increases that spread throughout photoreceptor terminals. We calculated immediately releasable pool (IRP) size and release efficiency in rods by deconvolving excitatory postsynaptic currents and presynaptic Ca2+ currents. Peak efficiency of ˜0.2 vesicles/channel was similar to that of cones (˜0.3 vesicles/channel). Efficiency in both cell types was not significantly affected by using weak endogenous Ca2+ buffering. However, weak Ca2+ buffering speeded Ca2+/calmodulin (CaM)-dependent replenishment of vesicles to ribbons in both rods and cones, thereby enhancing sustained release. In rods, weak Ca2+ buffering also amplified sustained release by enhancing CICR and CICR-stimulated release of vesicles at nonribbon sites. By contrast, elevating [Ca2+] at nonribbon sites in cones with weak Ca2+ buffering and by inhibiting Ca2+ extrusion did not trigger additional release, consistent with the notion that exocytosis from cones occurs exclusively at ribbons. The presence of weak endogenous Ca2+ buffering in rods and cones facilitates slow, sustained exocytosis by enhancing Ca2+/CaM-dependent replenishment of ribbons in both rods and cones and by stimulating nonribbon release triggered by CICR in rods. PMID:26416977

Sex-linked dominant

MedlinePlus

Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... can be either an autosomal chromosome or a sex chromosome. It also depends on whether the trait ...

Phosphorylation-independent suppression of light-activated visual pigment by arrestin in carp rods and cones.

PubMed

Tomizuka, Junko; Tachibanaki, Shuji; Kawamura, Satoru

2015-04-10

Visual pigment in photoreceptors is activated by light. Activated visual pigment (R*) is believed to be inactivated by phosphorylation of R* with subsequent binding of arrestin. There are two types of photoreceptors, rods and cones, in the vertebrate retina, and they express different subtypes of arrestin, rod and cone type. To understand the difference in the function between rod- and cone-type arrestin, we first identified the subtype of arrestins expressed in rods and cones in carp retina. We found that two rod-type arrestins, rArr1 and rArr2, are co-expressed in a rod and that a cone-type arrestin, cArr1, is expressed in blue- and UV-sensitive cones; the other cone-type arrestin, cArr2, is expressed in red- and green-sensitive cones. We quantified each arrestin subtype and estimated its concentration in the outer segment of a rod or a cone in the dark; they were ∼0.25 mm (rArr1 plus rArr2) in a rod and 0.6-0.8 mm (cArr1 or cArr2) in a cone. The effect of each arrestin was examined. In contrast to previous studies, both rod and cone arrestins suppressed the activation of transducin in the absence of visual pigment phosphorylation, and all of the arrestins examined (rArr1, rArr2, and cArr2) bound transiently to most probably nonphosphorylated R*. One rod arrestin, rArr2, bound firmly to phosphorylated pigment, and the other two, rArr1 and cArr2, once bound to phosphorylated R* but dissociated from it during incubation. Our results suggested a novel mechanism of arrestin effect on the suppression of the R* activity in both rods and cones. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Phosphorylation-independent Suppression of Light-activated Visual Pigment by Arrestin in Carp Rods and Cones*

PubMed Central

Tomizuka, Junko; Tachibanaki, Shuji; Kawamura, Satoru

2015-01-01

Visual pigment in photoreceptors is activated by light. Activated visual pigment (R*) is believed to be inactivated by phosphorylation of R* with subsequent binding of arrestin. There are two types of photoreceptors, rods and cones, in the vertebrate retina, and they express different subtypes of arrestin, rod and cone type. To understand the difference in the function between rod- and cone-type arrestin, we first identified the subtype of arrestins expressed in rods and cones in carp retina. We found that two rod-type arrestins, rArr1 and rArr2, are co-expressed in a rod and that a cone-type arrestin, cArr1, is expressed in blue- and UV-sensitive cones; the other cone-type arrestin, cArr2, is expressed in red- and green-sensitive cones. We quantified each arrestin subtype and estimated its concentration in the outer segment of a rod or a cone in the dark; they were ∼0.25 mm (rArr1 plus rArr2) in a rod and 0.6–0.8 mm (cArr1 or cArr2) in a cone. The effect of each arrestin was examined. In contrast to previous studies, both rod and cone arrestins suppressed the activation of transducin in the absence of visual pigment phosphorylation, and all of the arrestins examined (rArr1, rArr2, and cArr2) bound transiently to most probably nonphosphorylated R*. One rod arrestin, rArr2, bound firmly to phosphorylated pigment, and the other two, rArr1 and cArr2, once bound to phosphorylated R* but dissociated from it during incubation. Our results suggested a novel mechanism of arrestin effect on the suppression of the R* activity in both rods and cones. PMID:25713141

Four-Year Placebo-Controlled Trial of Docosahexaenoic Acid in X-Linked Retinitis Pigmentosa (DHAX Trial)

PubMed Central

Hoffman, Dennis R.; Hughbanks-Wheaton, Dianna K.; Pearson, N. Shirlene; Fish, Gary E.; Spencer, Rand; Takacs, Alison; Klein, Martin; Locke, Kirsten G.; Birch, David G.

2016-01-01

IMPORTANCE X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100 000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome. OBJECTIVE To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). DESIGN, SETTING, AND PARTICIPANTS A 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non–X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27). INTERVENTIONS All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. MAIN OUTCOMES AND MEASURES The primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence. RESULTS Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log µV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse

Learned arbitrary responses to light in mice without rods or cones

NASA Astrophysics Data System (ADS)

Mrosovsky, N.; Salmon, Peggy

2002-10-01

The aim of this investigation was to discover whether mice lacking classical photoreceptors (rods and cones) can nevertheless be trained to respond to light. Mice with the coneless (cl) transgene have an attenuated diphtheria toxin fused to a cone opsin promotor. Mutant mice homozygous for the retinal degeneration (rd) gene undergo loss of their rods. By mating these two strains, mice lacking both cones and rods can be generated (Lucas et al. 1999). Such coneless-rodless mice were able to use light as a signal to make a behavioural response to avoid impending shock. Nevertheless, especially initially, they used the light as a cue less often than wildtype controls, indicating that normally the rods and cones are used for such responses. However, other photoreceptors are able to take over this role to some extent. When the lights were covered with opaque material, the performance of rodless-coneless mice dropped to chance level, indicating that they had been using the light as a cue for avoidance.

A neuronal circuit for colour vision based on rod-cone opponency.

PubMed

Joesch, Maximilian; Meister, Markus

2016-04-14

In bright light, cone-photoreceptors are active and colour vision derives from a comparison of signals in cones with different visual pigments. This comparison begins in the retina, where certain retinal ganglion cells have 'colour-opponent' visual responses-excited by light of one colour and suppressed by another colour. In dim light, rod-photoreceptors are active, but colour vision is impossible because they all use the same visual pigment. Instead, the rod signals are thought to splice into retinal circuits at various points, in synergy with the cone signals. Here we report a new circuit for colour vision that challenges these expectations. A genetically identified type of mouse retinal ganglion cell called JAMB (J-RGC), was found to have colour-opponent responses, OFF to ultraviolet (UV) light and ON to green light. Although the mouse retina contains a green-sensitive cone, the ON response instead originates in rods. Rods and cones both contribute to the response over several decades of light intensity. Remarkably, the rod signal in this circuit is antagonistic to that from cones. For rodents, this UV-green channel may play a role in social communication, as suggested by spectral measurements from the environment. In the human retina, all of the components for this circuit exist as well, and its function can explain certain experiences of colour in dim lights, such as a 'blue shift' in twilight. The discovery of this genetically defined pathway will enable new targeted studies of colour processing in the brain.

Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X.

PubMed

Orosz, Orsolya; Rajta, István; Vajas, Attila; Takács, Lili; Csutak, Adrienne; Fodor, Mariann; Kolozsvári, Bence; Resch, Miklós; Sényi, Katalin; Lesch, Balázs; Szabó, Viktória; Berta, András; Balogh, István; Losonczy, Gergely

2017-03-01

Rare interchange haplotypes in exon 3 of the OPN1LW and OPN1MW opsin genes cause X-linked myopia, color vision defect, and cone dysfunction. The severity of the disease varies on a broad scale from nonsyndromic high myopia to blue cone monochromatism. Here, we describe a new genotype-phenotype correlation attributed to rare exon 3 interchange haplotypes simultaneously present in the long- and middle-wavelength sensitive opsin genes (L- and M-opsin genes). A multigenerational family with X-linked high myopia and cone dystrophy was investigated. Affected male patients had infantile onset myopia with normal visual acuity and color vision until their forties. Visual acuity decreased thereafter, along with the development of severe protan and deutan color vision defects. A mild decrease in electroretinography response of cone photoreceptors was detected in childhood, which further deteriorated in middle-aged patients. Rods were also affected, however, to a lesser extent than cones. Clinical exome sequencing identified the LVAVA and MVAVA toxic haplotypes in the OPN1LW and OPN1MW opsin genes, respectively. Here, we show that LVAVA haplotype of the OPN1LW gene and MVAVA haplotype of the OPN1MW gene cause apparently nonsyndromic high myopia in young patients but lead to progressive cone-rod dystrophy with deuteranopia and protanopia in middle-aged patients corresponding to a previously unknown disease course. To the best of our knowledge, this is the first report on the joint effect of these toxic haplotypes in the two opsin genes on chromosome X.

Evolutionary transformation of rod photoreceptors in the all-cone retina of a diurnal garter snake

PubMed Central

Schott, Ryan K.; Müller, Johannes; Yang, Clement G. Y.; Bhattacharyya, Nihar; Chan, Natalie; Xu, Mengshu; Morrow, James M.; Ghenu, Ana-Hermina; Loew, Ellis R.; Tropepe, Vincent; Chang, Belinda S. W.

2016-01-01

Vertebrate retinas are generally composed of rod (dim-light) and cone (bright-light) photoreceptors with distinct morphologies that evolved as adaptations to nocturnal/crepuscular and diurnal light environments. Over 70 years ago, the “transmutation” theory was proposed to explain some of the rare exceptions in which a photoreceptor type is missing, suggesting that photoreceptors could evolutionarily transition between cell types. Although studies have shown support for this theory in nocturnal geckos, the origins of all-cone retinas, such as those found in diurnal colubrid snakes, remain a mystery. Here we investigate the evolutionary fate of the rods in a diurnal garter snake and test two competing hypotheses: (i) that the rods, and their corresponding molecular machinery, were lost or (ii) that the rods were evolutionarily modified to resemble, and function, as cones. Using multiple approaches, we find evidence for a functional and unusually blue-shifted rhodopsin that is expressed in small single “cones.” Moreover, these cones express rod transducin and have rod ultrastructural features, providing strong support for the hypothesis that they are not true cones, as previously thought, but rather are modified rods. Several intriguing features of garter snake rhodopsin are suggestive of a more cone-like function. We propose that these cone-like rods may have evolved to regain spectral sensitivity and chromatic discrimination as a result of ancestral losses of middle-wavelength cone opsins in early snake evolution. This study illustrates how sensory evolution can be shaped not only by environmental constraints but also by historical contingency in forming new cell types with convergent functionality. PMID:26715746

Speed, spatial, and temporal tuning of rod and cone vision in mouse.

PubMed

Umino, Yumiko; Solessio, Eduardo; Barlow, Robert B

2008-01-02

Rods and cones subserve mouse vision over a 100 million-fold range of light intensity (-6 to 2 log cd m(-2)). Rod pathways tune vision to the temporal frequency of stimuli (peak, 0.75 Hz) and cone pathways to their speed (peak, approximately 12 degrees/s). Both pathways tune vision to the spatial components of stimuli (0.064-0.128 cycles/degree). The specific photoreceptor contributions were determined by two-alternative, forced-choice measures of contrast thresholds for optomotor responses of C57BL/6J mice with normal vision, Gnat2(cpfl3) mice without functional cones, and Gnat1-/- mice without functional rods. Gnat2(cpfl3) mice (threshold, -6.0 log cd m(-2)) cannot see rotating gratings above -2.0 log cd m(-2) (photopic vision), and Gnat1-/- mice (threshold, -4.0 log cd m(-2)) are blind below -4.0 log cd m(-2) (scotopic vision). Both genotypes can see in the transitional mesopic range (-4.0 to -2.0 log cd m(-2)). Mouse rod and cone sensitivities are similar to those of human. This parametric study characterizes the functional properties of the mouse visual system, revealing the rod and cone contributions to contrast sensitivity and to the temporal processing of visual stimuli.

Mesopic and Photopic Rod and Cone Photoreceptor-Driven Visual Processes in Mice With Long-Wavelength-Shifted Cone Pigments.

PubMed

Tsai, Tina I; Joachimsthaler, Anneka; Kremers, Jan

2017-10-01

The clearer divergence in spectral sensitivity between native rod and human L-cone (L*-cone) opsins in the transgenic Opn1lwLIAIS mouse (LIAIS) allows normal visual processes mediated by these photoreceptor subtypes to be isolated effectively using the silent substitution technique. The objective of this study was to further characterize the influence of mean luminance and temporal frequency on the functional properties of signals originating in each photoreceptor separately and independently of adaptation state in LIAIS mice. Electroretinographic (ERG) recordings to sine-wave rod and L*-cone modulation at different mean luminances (0.1-130.0 cd/m2) and temporal frequencies (6-26 Hz) were examined in anesthetized LIAIS (N = 17) and C57Bl/6 mice (N = 8). We report maximum rod-driven response with 8-Hz modulation at 0.1 to 0.5 cd/m2, which was almost four times larger than maximum cone-driven response at 8 Hz, 21.5 to 130 cd/m2. Over these optimal luminances, both rod- and cone-driven response amplitudes exhibited low-pass functions with similar frequency resolution limits, albeit their distinct luminance sensitivities. There were, however, two distinguishing features: (1) the frequency-dependent amplitude decrease of rod-driven responses was more profound, and (2) linear relationships describing rod-driven response phases as a function of stimulus frequency were steeper. Employing the silent substitution method with stimuli of appropriate luminance on the LIAIS mouse (as on human observers) increases the specificity, robustness, and scope to which photoreceptor-driven responses can be reliably assayed compared to the standard photoreceptor isolation methods.

Homeostatic Plasticity Mediated by Rod-Cone Gap Junction Coupling in Retinal Degenerative Dystrophic RCS Rats

PubMed Central

Hou, Baoke; Fu, Yan; Weng, Chuanhuang; Liu, Weiping; Zhao, Congjian; Yin, Zheng Qin

2017-01-01

Rod-cone gap junctions open at night to allow rod signals to pass to cones and activate the cone-bipolar pathway. This enhances the ability to detect large, dim objects at night. This electrical synaptic switch is governed by the circadian clock and represents a novel form of homeostatic plasticity that regulates retinal excitability according to network activity. We used tracer labeling and ERG recording in the retinae of control and retinal degenerative dystrophic RCS rats. We found that in the control animals, rod-cone gap junction coupling was regulated by the circadian clock via the modulation of the phosphorylation of the melatonin synthetic enzyme arylalkylamine N-acetyltransferase (AANAT). However, in dystrophic RCS rats, AANAT was constitutively phosphorylated, causing rod-cone gap junctions to remain open. A further b/a-wave ratio analysis revealed that dystrophic RCS rats had stronger synaptic strength between photoreceptors and bipolar cells, possibly because rod-cone gap junctions remained open. This was despite the fact that a decrease was observed in the amplitude of both a- and b-waves as a result of the progressive loss of rods during early degenerative stages. These results suggest that electric synaptic strength is increased during the day to allow cone signals to pass to the remaining rods and to be propagated to rod bipolar cells, thereby partially compensating for the weak visual input caused by the loss of rods. PMID:28473754

Psychophysical Measurement of Rod and Cone Thresholds in Stargardt Disease with Full-Field Stimuli

PubMed Central

Collison, Frederick T.; Fishman, Gerald A.; McAnany, J. Jason; Zernant, Jana; Allikmets, Rando

2014-01-01

Purpose To investigate psychophysical thresholds in Stargardt disease with the full-field stimulus test (FST). Methods Visual acuity (VA), spectral-domain optical coherence tomography (SD-OCT), full-field electroretinogram (ERG), and FST measurements were made in one eye of 24 patients with Stargardt disease. Dark-adapted rod FST thresholds were measured with short-wavelength stimuli, and cone FST thresholds were obtained from the cone plateau phase of dark adaptation using long-wavelength stimuli. Correlation coefficients were calculated for FST thresholds versus macular thickness, VA and ERG amplitudes. Results Stargardt patient FST cone thresholds correlated significantly with VA, macular thickness, and ERG cone-response amplitudes (all P<0.01). The patients’ FST rod thresholds correlated with ERG rod-response amplitudes (P<0.01), but not macular thickness (P=0.05). All Stargardt disease patients with flecks confined to the macula and most of the patients with flecks extending outside of the macula had normal FST thresholds. All patients with extramacular atrophic changes had elevated FST cone thresholds and most had elevated FST rod thresholds. Conclusion FST rod and cone threshold elevation in Stargardt disease patients correlated well with measures of structure and function, as well as ophthalmoscopic retinal appearance. FST appears to be a useful tool for assessing rod and cone function in Stargardt disease. PMID:24695063

Cone and Rod Loss in Stargardt Disease Revealed by Adaptive Optics Scanning Light Ophthalmoscopy

PubMed Central

Song, Hongxin; Rossi, Ethan A.; Latchney, Lisa; Bessette, Angela; Stone, Edwin; Hunter, Jennifer J.; Williams, David R.; Chung, Mina

2015-01-01

Importance Stargardt disease (STGD1) is characterized by macular atrophy and flecks in the retinal pigment epithelium. The causative ABCA4 gene encodes a protein localizing to photoreceptor outer segments. The pathologic steps by which ABCA4 mutations lead to clinically detectable retinal pigment epithelium changes remain unclear. We investigated early STGD1 using adaptive optics scanning light ophthalmoscopy. Observations Adaptive optics scanning light ophthalmoscopy imaging of 2 brothers with early STGD1 and their unaffected parents was compared with conventional imaging. Cone and rod spacing were increased in both patients (P <.001) with a dark cone appearance. No foveal cones were detected in the older brother. In the younger brother, foveal cones were enlarged with low density (peak cone density, 48.3 × 103 cones/mm2). The ratio of cone to rod spacing was increased in both patients, with greater divergence from normal approaching the foveal center, indicating that cone loss predominates centrally and rod loss increases peripherally. Both parents had normal photoreceptor mosaics. Genetic testing revealed 3 disease-causing mutations. Conclusions and Relevance This study provides in vivo images of rods and cones in STGD1. Although the primary clinical features of STGD1 are retinal pigment epithelial lesions, adaptive optics scanning light ophthalmoscopy reveals increased cone and rod spacing in areas that appear normal in conventional images, suggesting that photoreceptor loss precedes clinically detectable retinal pigment epithelial disease in STGD1. PMID:26247787

Biochemical Characterization of Cone Cyclic Nucleotide-gated (CNG) Channel Using the Infrared Fluorescence Detection System

PubMed Central

Ding, Xi-Qin; Matveev, Alexander; Singh, Anil; Komori, Naoka; Matsumoto, Hiroyuki

2012-01-01

Cone vision mediated by photoreceptor cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. Cone CNG channel is composed of two structurally related subunit types, CNGA3 and CNGB3. Naturally occurring mutations in cone CNG channel are associated with a variety of cone diseases including achromatopsia, progressive cone dystrophy, and some maculopathies. Nevertheless, our understanding of the structure of cone CNG channel is quite limited. This is, in part, due to the challenge of studying cones in a rod-dominant mammalian retina. We have demonstrated a robust expression of cone CNG channel and lack of rod CNG channel in the cone-dominant Nrl−/− retina and shown that the Nrl−/− mouse line is a valuable model to study cone CNG channel. This work examined the complex structure of cone CNG channel using infrared fluorescence Western detection combined with chemical cross-linking and blue native-PAGE. Our results suggest that the native cone CNG channel is a heterotetrameric complex likely at a stoichiometry of three CNGA3 and one CNGB3. PMID:22183405

In Vivo Two-Photon Fluorescence Kinetics of Primate Rods and Cones

PubMed Central

Sharma, Robin; Schwarz, Christina; Williams, David R.; Palczewska, Grazyna; Palczewski, Krzysztof; Hunter, Jennifer J.

2016-01-01

Purpose The retinoid cycle maintains vision by regenerating bleached visual pigment through metabolic events, the kinetics of which have been difficult to characterize in vivo. Two-photon fluorescence excitation has been used previously to track autofluorescence directly from retinoids and pyridines in the visual cycle in mouse and frog retinas, but the mechanisms of the retinoid cycle are not well understood in primates. Methods We developed a two-photon fluorescence adaptive optics scanning light ophthalmoscope dedicated to in vivo imaging in anesthetized macaques. Using pulsed light at 730 nm, two-photon fluorescence was captured from rods and cones during light and dark adaptation through the eye's pupil. Results The fluorescence from rods and cones increased with light exposure but at different rates. During dark adaptation, autofluorescence declined, with cone autofluorescence decreasing approximately 4 times faster than from rods. Rates of autofluorescence decrease in rods and cones were approximately 4 times faster than their respective rates of photopigment regeneration. Also, subsets of sparsely distributed cones were less fluorescent than their neighbors immediately following bleach at 565 nm and they were comparable with the S cone mosaic in density and distribution. Conclusions Although other molecules could be contributing, we posit that these fluorescence changes are mediated by products of the retinoid cycle. In vivo two-photon ophthalmoscopy provides a way to monitor noninvasively stages of the retinoid cycle that were previously inaccessible in the living primate eye. This can be used to assess objectively photoreceptor function in normal and diseased retinas. PMID:26903225

NMNAT1 variants cause cone and cone-rod dystrophy.

PubMed

Nash, Benjamin M; Symes, Richard; Goel, Himanshu; Dinger, Marcel E; Bennetts, Bruce; Grigg, John R; Jamieson, Robyn V

2018-03-01

Cone and cone-rod dystrophies (CD and CRD, respectively) are degenerative retinal diseases that predominantly affect the cone photoreceptors. The underlying disease gene is not known in approximately 75% of autosomal recessive cases. Variants in NMNAT1 cause a severe, early-onset retinal dystrophy called Leber congenital amaurosis (LCA). We report two patients where clinical phenotyping indicated diagnoses of CD and CRD, respectively. NMNAT1 variants were identified, with Case 1 showing an extremely rare homozygous variant c.[271G > A] p.(Glu91Lys) and Case 2 compound heterozygous variants c.[53 A > G];[769G > A] p.(Asn18Ser);(Glu257Lys). The detailed variant analysis, in combination with the observation of an associated macular atrophy phenotype, indicated that these variants were disease-causing. This report demonstrates that the variants in NMNAT1 may cause CD or CRD associated with macular atrophy. Genetic investigations of the patients with CD or CRD should include NMNAT1 in the genes examined.

Contributions of Rod and Cone Pathways to Retinal Direction Selectivity Through Development

PubMed Central

Rosa, Juliana M.; Morrie, Ryan D.; Baertsch, Hans C.

2016-01-01

Direction selectivity is a robust computation across a broad stimulus space that is mediated by activity of both rod and cone photoreceptors through the ON and OFF pathways. However, rods, S-cones, and M-cones activate the ON and OFF circuits via distinct pathways and the relative contribution of each to direction selectivity is unknown. Using a variety of stimulation paradigms, pharmacological agents, and knockout mice that lack rod transduction, we found that inputs from the ON pathway were critical for strong direction-selective (DS) tuning in the OFF pathway. For UV light stimulation, the ON pathway inputs to the OFF pathway originated with rod signaling, whereas for visible stimulation, the ON pathway inputs to the OFF pathway originated with both rod and M-cone signaling. Whole-cell voltage-clamp recordings revealed that blocking the ON pathway reduced directional tuning in the OFF pathway via a reduction in null-side inhibition, which is provided by OFF starburst amacrine cells (SACs). Consistent with this, our recordings from OFF SACs confirmed that signals originating in the ON pathway contribute to their excitation. Finally, we observed that, for UV stimulation, ON contributions to OFF DS tuning matured earlier than direct signaling via the OFF pathway. These data indicate that the retina uses multiple strategies for computing DS responses across different colors and stages of development. SIGNIFICANCE STATEMENT The retina uses parallel pathways to encode different features of the visual scene. In some cases, these distinct pathways converge on circuits that mediate a distinct computation. For example, rod and cone pathways enable direction-selective (DS) ganglion cells to encode motion over a wide range of light intensities. Here, we show that although direction selectivity is robust across light intensities, motion discrimination for OFF signals is dependent upon ON signaling. At eye opening, ON directional tuning is mature, whereas OFF DS tuning is

Dark Light, Rod Saturation, and the Absolute and Incremental Sensitivity of Mouse Cone Vision

PubMed Central

Naarendorp, Frank; Esdaille, Tricia M.; Banden, Serenity M.; Andrews-Labenski, John; Gross, Owen P.; Pugh, Edward N.

2012-01-01

Visual thresholds of mice for the detection of small, brief targets were measured with a novel behavioral methodology in the dark and in the presence of adapting lights spanning ∼8 log10 units of intensity. To help dissect the contributions of rod and cone pathways, both wild-type mice and mice lacking rod (Gnat1−/−) or cone (Gnat2cpfl3) function were studied. Overall, the visual sensitivity of mice was found to be remarkably similar to that of the human peripheral retina. Rod absolute threshold corresponded to 12-15 isomerized pigment molecules (R*) in image fields of 800 to 3000 rods. Rod “dark light” (intrinsic retinal noise in darkness) corresponded to that estimated previously from single-cell recordings, 0.012R*s−1rod−1, indicating that spontaneous thermalisomerizations are responsible. Psychophysical rod saturation was measured for the first time in a nonhman species and found to be very similar to that of the human rod monochromat. Cone threshold corresponded to ∼5 R* cone−1 in an image field of 280 cones. Cone dark light was equivalent to ∼5000 R*s−1 cone−1, consistent with primate single-cell data but 100-fold higher than predicted by recent measurements of the rate of thermal isomerization of mouse cone opsins, indicating that nonopsin sources of noise determine cone threshold. The new, fully automated behavioral method is based on the ability of mice to learn to interrupt spontaneous wheel running on the presentation of a visual cue and provides an efficient and highly reliable means of examining visual function in naturally behaving normal and mutant mice. PMID:20844144

Rod- versus cone-driven ERGs at different stimulus sizes in normal subjects and retinitis pigmentosa patients.

PubMed

Aher, Avinash J; McKeefry, Declan J; Parry, Neil R A; Maguire, John; Murray, I J; Tsai, Tina I; Huchzermeyer, Cord; Kremers, Jan

2018-02-01

To study how rod- and cone-driven responses depend on stimulus size in normal subjects and patients with retinitis pigmentosa (RP), and to show that comparisons between responses to full-field (FF) and smaller stimuli can be useful in diagnosing and monitoring disorders of the peripheral retina without the need for lengthy dark adaptation periods. The triple silent substitution technique was used to isolate L-cone-, M-cone- and rod-driven ERGs with 19, 18 and 33% photoreceptor contrasts, respectively, under identical mean luminance conditions. Experiments were conducted on five normal subjects and three RP patients. ERGs on control subjects were recorded at nine different temporal frequencies (between 2 and 60 Hz) for five different stimulus sizes: FF, 70°, 60°, 50° and 40° diameter circular stimuli. Experiments on RP patients involved rod- and L-cone-driven ERG measurements with FF and 40° stimuli at 8 and 48 Hz. Response amplitudes were defined as those of the first harmonic component after Fourier analysis. In normal subjects, rod-driven responses displayed a fundamentally different behavior than cone-driven responses, particularly at low temporal frequencies. At low and intermediate temporal frequencies (≤ 12 Hz), rod-driven signals increased by a factor of about four when measured with smaller stimuli. In contrast, L- and M-cone-driven responses in this frequency region did not change substantially with stimulus size. At high temporal frequencies (≥ 24 Hz), both rod- and cone-driven response amplitudes decreased with decreasing stimulus size. Signals obtained from rod-isolating stimuli under these conditions are likely artefactual. Interestingly, in RP patients, both rod-driven and L-cone-driven ERGs were similar using 40° and FF stimuli. The increased responses with smaller stimuli in normal subjects to rod-isolating stimuli indicate that a fundamentally different mechanism drives the ERGs in comparison with the cone-driven responses. We

Prominin-1 Localizes to the Open Rims of Outer Segment Lamellae in Xenopus laevis Rod and Cone Photoreceptors

PubMed Central

Han, Zhou; Anderson, David W.

2012-01-01

Purpose. Prominin-1 expresses in rod and cone photoreceptors. Mutations in the prominin-1 gene cause retinal degeneration in humans. In this study, the authors investigated the expression and subcellular localization of xlProminin-1 protein, the Xenopus laevis ortholog of prominin-1, in rod and cone photoreceptors of this frog. Methods. Antibodies specific for xlProminin-1 were generated. Immunoblotting was used to study the expression and posttranslational processing of xlProminin-1 protein. Immunocytochemical light and electron microscopy and transgenesis were used to study the subcellular distribution of xlProminin-1. Results. xlProminin-1 is expressed and is subject to posttranslational proteolytic processing in the retina, brain, and kidney. xlProminin-1 is differently expressed and localized in outer segments of rod and cone photoreceptors of X. laevis. Antibodies specific for the N or C termini of xlProminin-1 labeled the open rims of lamellae of cone outer segments (COS) and the open lamellae at the base of rod outer segments (ROS). By contrast, anti–peripherin-2/rds antibody, Xper5A11, labeled the closed rims of cone lamellae adjacent to the ciliary axoneme and the rims of the closed ROS disks. The extent of labeling of the basal ROS by anti–xlProminin-1 antibodies varied with the light cycle in this frog. The entire ROS was also faintly labeled by both antibodies, a result that contrasts with the current notion that prominin-1 localizes only to the basal ROS. Conclusions. These findings suggest that xlProminin-1 may serve as an anti–fusogenic factor in the regulation of disk morphogenesis and may help to maintain the open lamellar structure of basal ROS and COS disks in X. laevis photoreceptors. PMID:22076989

Bcl-xL-mediated remodeling of rod and cone synaptic mitochondria after postnatal lead exposure: electron microscopy, tomography and oxygen consumption.

PubMed

Perkins, Guy A; Scott, Ray; Perez, Alex; Ellisman, Mark H; Johnson, Jerry E; Fox, Donald A

2012-01-01

Postnatal lead exposure produces rod-selective and Bax-mediated apoptosis, decreased scotopic electroretinograms (ERGs), and scotopic and mesopic vision deficits in humans and/or experimental animals. Rod, but not cone, inner segment mitochondria were considered the primary site of action. However, photoreceptor synaptic mitochondria were not examined. Thus, our experiments investigated the structural and functional effects of environmentally relevant postnatal lead exposure on rod spherule and cone pedicle mitochondria and whether Bcl-xL overexpression provided neuroprotection. C57BL/6N mice pups were exposed to lead only during lactation via dams drinking water containing lead acetate. The blood [Pb] at weaning was 20.6±4.7 µg/dl, which decreased to the control value by 2 months. To assess synaptic mitochondrial structural differences and vulnerability to lead exposure, wild-type and transgenic mice overexpressing Bcl-xL in photoreceptors were used. Electron microscopy, three-dimensional electron tomography, and retinal and photoreceptor synaptic terminal oxygen consumption (QO(2)) studies were conducted in adult control, Bcl-xL, lead, and Bcl-xL/lead mice. The spherule and pedicle mitochondria in lead-treated mice were swollen, and the cristae structure was markedly changed. In the lead-treated mice, the mitochondrial cristae surface area and volume (abundance: measure correlated with ATP (ATP) synthesis) were decreased in the spherules and increased in the pedicles. Pedicles also had an increased number of crista segments per volume. In the lead-treated mice, the number of segments/crista and fraction of cristae with multiple segments (branching) similarly increased in spherule and pedicle mitochondria. Lead-induced remodeling of spherule mitochondria produced smaller cristae with more branching, whereas pedicle mitochondria had larger cristae with more branching and increased crista junction (CJ) diameter. Lead decreased dark- and light-adapted photoreceptor

Adaptation of cone pigments found in green rods for scotopic vision through a single amino acid mutation

PubMed Central

Kojima, Keiichi; Matsutani, Yuki; Yamashita, Takahiro; Yanagawa, Masataka; Imamoto, Yasushi; Yamano, Yumiko; Wada, Akimori; Hisatomi, Osamu; Nishikawa, Kanto; Sakurai, Keisuke; Shichida, Yoshinori

2017-01-01

Most vertebrate retinas contain a single type of rod for scotopic vision and multiple types of cones for photopic and color vision. The retinas of certain amphibian species uniquely contain two types of rods: red rods, which express rhodopsin, and green rods, which express a blue-sensitive cone pigment (M1/SWS2 group). Spontaneous activation of rhodopsin induced by thermal isomerization of the retinal chromophore has been suggested to contribute to the rod’s background noise, which limits the visual threshold for scotopic vision. Therefore, rhodopsin must exhibit low thermal isomerization rate compared with cone visual pigments to adapt to scotopic condition. In this study, we determined whether amphibian blue-sensitive cone pigments in green rods exhibit low thermal isomerization rates to act as rhodopsin-like pigments for scotopic vision. Anura blue-sensitive cone pigments exhibit low thermal isomerization rates similar to rhodopsin, whereas Urodela pigments exhibit high rates like other vertebrate cone pigments present in cones. Furthermore, by mutational analysis, we identified a key amino acid residue, Thr47, that is responsible for the low thermal isomerization rates of Anura blue-sensitive cone pigments. These results strongly suggest that, through this mutation, anurans acquired special blue-sensitive cone pigments in their green rods, which could form the molecular basis for scotopic color vision with normal red rods containing green-sensitive rhodopsin. PMID:28484015

Rod-cone based color vision in seals under photopic conditions.

PubMed

Oppermann, Daniela; Schramme, Jürgen; Neumeyer, Christa

2016-08-01

Marine mammals have lost the ability to express S-cone opsin, and possess only one type of M/L-cone in addition to numerous rods. As they are cone monochromats they should be color blind. However, early behavioral experiments with fur seals and sea lions indicated discrimination ability between many shades of grey and blue or green. On the other hand, most recent training experiments with harbor seals under "mesopic" conditions demonstrated rod based color blindness (Scholtyssek et al., 2015). In our experiments we trained two harbor seals (Phoca vitulina) and two South African fur seals (Arctocephalus pusillus) with surface colors under photopic conditions. The seals had to detect a triangle on grey background shown on one of three test fields while the other two test fields were homogeneously grey. In a first series of experiments we determined brightness detection. We found a luminance contrast of >3% sufficient for correctly choosing the triangle. In the tests for color vision the triangle was blue, green or yellow in grey surround. The results show that the animals could see the colored triangle despite minimal or zero brightness contrast. Thus, seals have color vision based on the contribution of cones and rods even in bright daylight. Copyright © 2016 Elsevier Ltd. All rights reserved.

CNGA3 deficiency affects cone synaptic terminal structure and function and leads to secondary rod dysfunction and degeneration.

PubMed

Xu, Jianhua; Morris, Lynsie M; Michalakis, Stylianos; Biel, Martin; Fliesler, Steven J; Sherry, David M; Ding, Xi-Qin

2012-03-01

To investigate rod function and survival after cone dysfunction and degeneration in a mouse model of cone cyclic nucleotide-gated (CNG) channel deficiency. Rod function and survival in mice with cone CNG channel subunit CNGA3 deficiency (CNGA3-/- mice) were evaluated by electroretinographic (ERG), morphometric, and Western blot analyses. The arrangement, integrity, and ultrastructure of photoreceptor terminals were investigated by immunohistochemistry and electron microscopy. The authors found loss of cone function and cone death accompanied by impairment of rods and rod-driven signaling in CNGA3-/- mice. Scotopic ERG b-wave amplitudes were reduced by 15% at 1 month, 30% at 6 months, and 40% at 9 months and older, while scotopic a-wave amplitudes were decreased by 20% at 9 months, compared with ERGs of age-matched wild-type mice. Outer nuclear layer thickness in CNGA3-/- retina was reduced by 15% at 12 months compared with age-matched wild-type controls. This was accompanied by a 30%-40% reduction in expression of rod-specific proteins, including rhodopsin, rod transducin α-subunit, and glutamic acid-rich protein (GARP). Cone terminals in the CNGA3-/- retina showed a progressive loss of neurochemical and ultrastructural integrity. Abnormalities were observed as early as 1 month. Disorganized rod terminal ultrastructure was noted by 12 months. These findings demonstrate secondary rod impairment and degeneration after cone degeneration in mice with cone CNG channel deficiency. Loss of cone phototransduction accompanies the compromised integrity of cone terminals. With time, rod synaptic structure, function, and viability also become compromised.

CNGA3 Deficiency Affects Cone Synaptic Terminal Structure and Function and Leads to Secondary Rod Dysfunction and Degeneration

PubMed Central

Xu, Jianhua; Morris, Lynsie M.; Michalakis, Stylianos; Biel, Martin; Fliesler, Steven J.; Sherry, David M.

2012-01-01

Purpose. To investigate rod function and survival after cone dysfunction and degeneration in a mouse model of cone cyclic nucleotide-gated (CNG) channel deficiency. Methods. Rod function and survival in mice with cone CNG channel subunit CNGA3 deficiency (CNGA3−/− mice) were evaluated by electroretinographic (ERG), morphometric, and Western blot analyses. The arrangement, integrity, and ultrastructure of photoreceptor terminals were investigated by immunohistochemistry and electron microscopy. Results. The authors found loss of cone function and cone death accompanied by impairment of rods and rod-driven signaling in CNGA3−/− mice. Scotopic ERG b-wave amplitudes were reduced by 15% at 1 month, 30% at 6 months, and 40% at 9 months and older, while scotopic a-wave amplitudes were decreased by 20% at 9 months, compared with ERGs of age-matched wild-type mice. Outer nuclear layer thickness in CNGA3−/− retina was reduced by 15% at 12 months compared with age-matched wild-type controls. This was accompanied by a 30%–40% reduction in expression of rod-specific proteins, including rhodopsin, rod transducin α-subunit, and glutamic acid-rich protein (GARP). Cone terminals in the CNGA3−/− retina showed a progressive loss of neurochemical and ultrastructural integrity. Abnormalities were observed as early as 1 month. Disorganized rod terminal ultrastructure was noted by 12 months. Conclusions. These findings demonstrate secondary rod impairment and degeneration after cone degeneration in mice with cone CNG channel deficiency. Loss of cone phototransduction accompanies the compromised integrity of cone terminals. With time, rod synaptic structure, function, and viability also become compromised. PMID:22247469

Melanopsin changes in neonatal albino rat independent of rods and cones.

PubMed

Hannibal, Jens; Georg, Birgitte; Fahrenkrug, Jan

2007-01-08

Intrinsically photosensitive retinal ganglion cells employ the photopigment melanopsin and provide light information to brain areas responsible for the regulation of circadian rhythms. The expression of melanopsin is regulated by environmental illumination, but it remains to be clarified whether the rods and cones are involved. Here, we examined the influence of 5 days of constant light and dark conditions on melanopsin mRNA and protein expression in newborn albino rats, in which functional rods and cones have not yet been developed. We found that the melanopsin mRNA level was unaffected, whereas the melanopsin protein level was more than two-fold higher in the darkness-adapted group than in pups raised in constant light. In pups raised during 12 : 12 h light/dark cycles, the melanopsin protein level was significantly higher during the day than at night. Our findings indicate that melanopsin protein changes are independent of input from the rods and cones.

Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy.

PubMed

Lhériteau, Elsa; Petit, Lolita; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Libeau, Lyse; Mendes-Madeira, Alexandra; Guihal, Caroline; François, Achille; Guyon, Richard; Provost, Nathalie; Lemoine, Françoise; Papal, Samantha; El-Amraoui, Aziz; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

2014-02-01

For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod-cone dystrophies but not in large models of progressive cone-rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone-rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18-72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22-29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone-rod dystrophy provides great promise for human treatment.

Spatiotemporal regulation of ATP and Ca2+ dynamics in vertebrate rod and cone ribbon synapses

PubMed Central

Johnson, Jerry E.; Perkins, Guy A.; Giddabasappa, Anand; Chaney, Shawntay; Xiao, Weimin; White, Andrew D.; Brown, Joshua M.; Waggoner, Jenna; Ellisman, Mark H.

2007-01-01

Purpose In conventional neurons, Ca2+ enters presynaptic terminals during an action potential and its increased local concentration triggers transient exocytosis. In contrast, vertebrate photoreceptors are nonspiking neurons that maintain sustained depolarization and neurotransmitter release from ribbon synapses in darkness and produce light-dependent graded hyperpolarizing responses. Rods transmit single photon responses with high fidelity, whereas cones are less sensitive and exhibit faster response kinetics. These differences are likely due to variations in presynaptic Ca2+ dynamics. Metabolic coupling and cross-talk between mitochondria, endoplasmic reticulum (ER), plasma membrane Ca2+ ATPase (PMCA), and Na+-Ca2+ exchanger (NCX) coordinately control presynaptic ATP production and Ca2+ dynamics. The goal of our structural and functional studies was to determine the spatiotemporal regulation of ATP and Ca2+ dynamics in rod spherules and cone pedicles. Methods Central retina tissue from C57BL/6 mice was used. Laser scanning confocal microscopy (LSCM) experiments were conducted on fixed-frozen vertical sections. Primary antibodies were selected for their tissue/cellular specificity and ability to recognize single, multiple or all splice variants of selected isoforms. Electron microscopy (EM) and 3-D electron tomography (ET) studies used our standard procedures on thin- and thick-sectioned retinas, respectively. Calibrated fluo-3-Ca2+ imaging experiments of dark- and light-adapted rod and cone terminals in retinal slices were conducted. Results Confocal microscopy showed that mitochondria, ER, PMCA, and NCX1 exhibited distinct retinal lamination patterns and differential distribution in photoreceptor synapses. Antibodies for three distinct mitochondrial compartments differentially labeled retinal areas with high metabolic demand: rod and cone inner segments, previously undescribed cone juxtanuclear mitochondria and the two plexiform layers. Rod spherule membranes

Spatiotemporal regulation of ATP and Ca2+ dynamics in vertebrate rod and cone ribbon synapses.

PubMed

Johnson, Jerry E; Perkins, Guy A; Giddabasappa, Anand; Chaney, Shawntay; Xiao, Weimin; White, Andrew D; Brown, Joshua M; Waggoner, Jenna; Ellisman, Mark H; Fox, Donald A

2007-06-15

In conventional neurons, Ca2+ enters presynaptic terminals during an action potential and its increased local concentration triggers transient exocytosis. In contrast, vertebrate photoreceptors are nonspiking neurons that maintain sustained depolarization and neurotransmitter release from ribbon synapses in darkness and produce light-dependent graded hyperpolarizing responses. Rods transmit single photon responses with high fidelity, whereas cones are less sensitive and exhibit faster response kinetics. These differences are likely due to variations in presynaptic Ca2+ dynamics. Metabolic coupling and cross-talk between mitochondria, endoplasmic reticulum (ER), plasma membrane Ca2+ ATPase (PMCA), and Na+-Ca2+ exchanger (NCX) coordinately control presynaptic ATP production and Ca2+ dynamics. The goal of our structural and functional studies was to determine the spatiotemporal regulation of ATP and Ca2+ dynamics in rod spherules and cone pedicles. Central retina tissue from C57BL/6 mice was used. Laser scanning confocal microscopy (LSCM) experiments were conducted on fixed-frozen vertical sections. Primary antibodies were selected for their tissue/cellular specificity and ability to recognize single, multiple or all splice variants of selected isoforms. Electron microscopy (EM) and 3-D electron tomography (ET) studies used our standard procedures on thin- and thick-sectioned retinas, respectively. Calibrated fluo-3-Ca2+ imaging experiments of dark- and light-adapted rod and cone terminals in retinal slices were conducted. Confocal microscopy showed that mitochondria, ER, PMCA, and NCX1 exhibited distinct retinal lamination patterns and differential distribution in photoreceptor synapses. Antibodies for three distinct mitochondrial compartments differentially labeled retinal areas with high metabolic demand: rod and cone inner segments, previously undescribed cone juxtanuclear mitochondria and the two plexiform layers. Rod spherule membranes uniformly and intensely

GUCY2D Cone-Rod Dystrophy-6 Is a "Phototransduction Disease" Triggered by Abnormal Calcium Feedback on Retinal Membrane Guanylyl Cyclase 1.

PubMed

Sato, Shinya; Peshenko, Igor V; Olshevskaya, Elena V; Kefalov, Vladimir J; Dizhoor, Alexander M

2018-03-21

The Arg838Ser mutation in retinal membrane guanylyl cyclase 1 (RetGC1) has been linked to autosomal dominant cone-rod dystrophy type 6 (CORD6). It is believed that photoreceptor degeneration is caused by the altered sensitivity of RetGC1 to calcium regulation via guanylyl cyclase activating proteins (GCAPs). To determine the mechanism by which this mutation leads to degeneration, we investigated the structure and function of rod photoreceptors in two transgenic mouse lines, 362 and 379, expressing R838S RetGC1. In both lines, rod outer segments became shorter than in their nontransgenic siblings by 3-4 weeks of age, before the eventual photoreceptor degeneration. Despite the shortening of their outer segments, the dark current of transgenic rods was 1.5-2.2-fold higher than in nontransgenic controls. Similarly, the dim flash response amplitude in R838S + rods was larger, time to peak was delayed, and flash sensitivity was increased, all suggesting elevated dark-adapted free cGMP in transgenic rods. In rods expressing R838S RetGC1, dark-current noise increased and the exchange current, detected after a saturating flash, became more pronounced. These results suggest disrupted Ca 2+ phototransduction feedback and abnormally high free-Ca 2+ concentration in the outer segments. Notably, photoreceptor degeneration, which typically occurred after 3 months of age in R838S RetGC1 transgenic mice in GCAP1,2 +/+ or GCAP1,2 +/- backgrounds, was prevented in GCAP1,2 -/- mice lacking Ca 2+ feedback to guanylyl cyclase. In summary, the dysregulation of guanylyl cyclase in RetGC1-linked CORD6 is a "phototransduction disease," which means it is associated with increased free-cGMP and Ca 2+ levels in photoreceptors. SIGNIFICANCE STATEMENT In a mouse model expressing human membrane guanylyl cyclase 1 (RetGC1, GUCY2D ), a mutation associated with early progressing congenital blindness, cone-rod dystrophy type 6 (CORD6), deregulates calcium-sensitive feedback of phototransduction to

Pushing the limits of photoreception in twilight conditions: The rod-like cone retina of the deep-sea pearlsides.

PubMed

de Busserolles, Fanny; Cortesi, Fabio; Helvik, Jon Vidar; Davies, Wayne I L; Templin, Rachel M; Sullivan, Robert K P; Michell, Craig T; Mountford, Jessica K; Collin, Shaun P; Irigoien, Xabier; Kaartvedt, Stein; Marshall, Justin

2017-11-01

Most vertebrates have a duplex retina comprising two photoreceptor types, rods for dim-light (scotopic) vision and cones for bright-light (photopic) and color vision. However, deep-sea fishes are only active in dim-light conditions; hence, most species have lost their cones in favor of a simplex retina composed exclusively of rods. Although the pearlsides, Maurolicus spp., have such a pure rod retina, their behavior is at odds with this simplex visual system. Contrary to other deep-sea fishes, pearlsides are mostly active during dusk and dawn close to the surface, where light levels are intermediate (twilight or mesopic) and require the use of both rod and cone photoreceptors. This study elucidates this paradox by demonstrating that the pearlside retina does not have rod photoreceptors only; instead, it is composed almost exclusively of transmuted cone photoreceptors. These transmuted cells combine the morphological characteristics of a rod photoreceptor with a cone opsin and a cone phototransduction cascade to form a unique photoreceptor type, a rod-like cone, specifically tuned to the light conditions of the pearlsides' habitat (blue-shifted light at mesopic intensities). Combining properties of both rods and cones into a single cell type, instead of using two photoreceptor types that do not function at their full potential under mesopic conditions, is likely to be the most efficient and economical solution to optimize visual performance. These results challenge the standing paradigm of the function and evolution of the vertebrate duplex retina and emphasize the need for a more comprehensive evaluation of visual systems in general.

Pushing the limits of photoreception in twilight conditions: The rod-like cone retina of the deep-sea pearlsides

PubMed Central

de Busserolles, Fanny; Cortesi, Fabio; Helvik, Jon Vidar; Davies, Wayne I. L.; Templin, Rachel M.; Sullivan, Robert K. P.; Michell, Craig T.; Mountford, Jessica K.; Collin, Shaun P.; Irigoien, Xabier; Kaartvedt, Stein; Marshall, Justin

2017-01-01

Most vertebrates have a duplex retina comprising two photoreceptor types, rods for dim-light (scotopic) vision and cones for bright-light (photopic) and color vision. However, deep-sea fishes are only active in dim-light conditions; hence, most species have lost their cones in favor of a simplex retina composed exclusively of rods. Although the pearlsides, Maurolicus spp., have such a pure rod retina, their behavior is at odds with this simplex visual system. Contrary to other deep-sea fishes, pearlsides are mostly active during dusk and dawn close to the surface, where light levels are intermediate (twilight or mesopic) and require the use of both rod and cone photoreceptors. This study elucidates this paradox by demonstrating that the pearlside retina does not have rod photoreceptors only; instead, it is composed almost exclusively of transmuted cone photoreceptors. These transmuted cells combine the morphological characteristics of a rod photoreceptor with a cone opsin and a cone phototransduction cascade to form a unique photoreceptor type, a rod-like cone, specifically tuned to the light conditions of the pearlsides’ habitat (blue-shifted light at mesopic intensities). Combining properties of both rods and cones into a single cell type, instead of using two photoreceptor types that do not function at their full potential under mesopic conditions, is likely to be the most efficient and economical solution to optimize visual performance. These results challenge the standing paradigm of the function and evolution of the vertebrate duplex retina and emphasize the need for a more comprehensive evaluation of visual systems in general. PMID:29134201

A sign-reversing pathway from rods to double and single cones in the retina of the tiger salamander.

PubMed

Attwell, D; Werblin, F S; Wilson, M; Wu, S M

1983-03-01

Signal transmission between rods and cones was studied by passing current into a rod and recording the voltage response in a nearby double or single cone and vice versa. Two types of rod-cone interaction were found. Between immediately adjacent rods and cones, passage of current into either receptor elicited in the other receptor a sustained voltage response of the same sign as the injected current. These signals were still seen in the presence of Co2+, and are probably mediated by the electrical synapses which have been seen anatomically between adjacent rods and cones. In addition to this short-range sign-preserving interaction, passing current into a rod elicited a transient sign-inverted signal in cones up to at least 80 micron from the injected rod. No such response was seen in rods for current injection into cones. This signal was greatly reduced by Co2+ ions. Hyperpolarization of the cone to about -65 mV, with about 0.1 nA current, reversed this signal, which is presumed to be mediated by a chemical synaptic input to cones. Light flashes suppressed the sign-inverted signal for a period which was longer for brighter flashes. The time of reappearance of the signal was correlated with the return of the rod and horizontal cell potentials to their dark levels. This suppression could also be produced by an annulus of light which produced no light response in the receptors at the centre of the annulus, but which did polarize horizontal cells under the centre of the annulus. The wave form of the sign-inverted signal was similar to that produced in horizontal cells by current injection into rods, but of opposite sign. If an electrode was left in a cone for some time, the normal hyperpolarizing light response diminished, leaving a depolarizing response produced, presumably, by feed-back from horizontal cells. This signal was reversed when the cone was hyperpolarized with about 0.1 nA current. These data suggest that the sign-inverted response is mediated by feed

Effect of stimulus size and luminance on the rod-, cone-, and melanopsin-mediated pupillary light reflex

PubMed Central

Park, Jason C.; McAnany, J. Jason

2015-01-01

This study determined if the pupillary light reflex (PLR) driven by brief stimulus presentations can be accounted for by the product of stimulus luminance and area (i.e., corneal flux density, CFD) under conditions biased toward the rod, cone, and melanopsin pathways. Five visually normal subjects participated in the study. Stimuli consisted of 1-s short- and long-wavelength flashes that spanned a large range of luminance and angular subtense. The stimuli were presented in the central visual field in the dark (rod and melanopsin conditions) and against a rod-suppressing short-wavelength background (cone condition). Rod- and cone-mediated PLRs were measured at the maximum constriction after stimulus onset whereas the melanopsin-mediated PLR was measured 5–7 s after stimulus offset. The rod- and melanopsin-mediated PLRs were well accounted for by CFD, such that doubling the stimulus luminance had the same effect on the PLR as doubling the stimulus area. Melanopsin-mediated PLRs were elicited only by short-wavelength, large (>16°) stimuli with luminance greater than 10 cd/m2, but when present, the melanopsin-mediated PLR was well accounted for by CFD. In contrast, CFD could not account for the cone-mediated PLR because the PLR was approximately independent of stimulus size but strongly dependent on stimulus luminance. These findings highlight important differences in how stimulus luminance and size combine to govern the PLR elicited by brief flashes under rod-, cone-, and melanopsin-mediated conditions. PMID:25788707

LOW CONDUCTANCE HCN1 ION CHANNELS AUGMENT THE FREQUENCY RESPONSE OF ROD AND CONE PHOTORECEPTORS

PubMed Central

Barrow, Andrew J.; Wu, Samuel M.

2009-01-01

Hyperpolarization-activated cyclic nucleotide gated (HCN) ion channels are expressed in several tissues throughout the body, including the heart, the CNS, and the retina. HCN channels are found in many neurons in the retina, but their most established role is in generating the hyperpolarization-activated current, Ih, in photoreceptors. This current makes the light response of rod and cone photoreceptors more transient, an effect similar to that of a high-pass filter. A unique property of HCN channels is their small single channel current, which is below the thermal noise threshold of measuring electronics. We use nonstationary fluctuation analysis (NSFA) in the intact retina to estimate the conductance of single HCN channels, revealing a conductance of approximately 650 fS in both rod and cone photoreceptors. We also analyze the properties of HCN channels in salamander rods and cones, from the biophysical to the functional level, showing that HCN1 is the predominant isoform in both cells, and demonstrate how HCN1 channels speed up the light response of both rods and cones under distinct adaptational conditions. We show that in rods and cones, HCN channels increase the natural frequency response of single cells by modifying the photocurrent input, which is limited in its frequency response by the speed of a molecular signaling cascade. In doing so, HCN channels form the first of several systems in the retina that augment the speed of the visual response, allowing an animal to perceive visual stimuli that change more quickly than the underlying photocurrent. PMID:19420251

A study of the human rod and cone electroretinogram a-wave component

NASA Astrophysics Data System (ADS)

Barraco, R.; Persano Adorno, D.; Bellomonte, L.; Brai, M.

2009-03-01

The study of the electrical response of the retina to a luminous stimulus is one of the main fields of research in ocular electrophysiology. The features of the first component (a-wave) of the retinal response reflect the functional integrity of the two populations of photoreceptors: rods and cones. We fit the a-wave for pathological subjects with functions that account for possible mechanisms governing the kinetics of the photoreceptors. The paper extends a previous analysis, carried out for normal subjects, in which both populations are active, to patients affected by two particular diseases that reduce the working populations to only one. The pathologies investigated are Achromatopsia, a cone disease, and Congenital Stationary Night Blindness, a rod problem. We present evidence that the analysis of a pathological a-wave can be employed to quantitatively measure either cone or rod activities and to test hypotheses about their responses. The results show that the photoreceptoral responses differ in the two cases and functions implying a different number of photocascade stages are necessary to achieve a correct modeling of the early phototransduction process. Numerical values of the parameters characterizing the best-fit functions are given and discussed.

Bilateral Symmetry of Visual Function Loss in Cone-Rod Dystrophies.

PubMed

Galli-Resta, Lucia; Falsini, Benedetto; Rossi, Giuseppe; Piccardi, Marco; Ziccardi, Lucia; Fadda, Antonello; Minnella, Angelo; Marangoni, Dario; Placidi, Giorgio; Campagna, Francesca; Abed, Edoardo; Bertelli, Matteo; Zuntini, Monia; Resta, Giovanni

2016-07-01

To investigate bilateral symmetry of visual impairment in cone-rod dystrophy (CRD) patients and understand the feasibility of clinical trial designs treating one eye and using the untreated eye as an internal control. This was a retrospective study of visual function loss measures in 436 CRD patients followed at the Ophthalmology Department of the Catholic University in Rome. Clinical measures considered were best-corrected visual acuity, focal macular cone electroretinogram (fERG), and Ganzfeld cone-mediated and rod-mediated electroretinograms. Interocular agreement in each of these clinical indexes was assessed by t- and Wilcoxon tests for paired samples, structural (Deming) regression analysis, and intraclass correlation. Baseline and follow-up measures were analyzed. A separate analysis was performed on the subset of 61 CRD patients carrying likely disease-causing mutations in the ABCA4 gene. Statistical tests show a very high degree of bilateral symmetry in the extent and progression of visual impairment in the fellow eyes of CRD patients. These data contribute to a better understanding of CRDs and support the feasibility of clinical trial designs involving unilateral eye treatment with the use of fellow eye as internal control.

Aerobic Glycolysis Is Essential for Normal Rod Function and Controls Secondary Cone Death in Retinitis Pigmentosa.

PubMed

Petit, Lolita; Ma, Shan; Cipi, Joris; Cheng, Shun-Yun; Zieger, Marina; Hay, Nissim; Punzo, Claudio

2018-05-29

Aerobic glycolysis accounts for ∼80%-90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic stress conditions such as those encountered in retinitis pigmentosa, where the loss of rods causes a nutrient shortage in cones. The data support a model where aerobic glycolysis in PRs is not a necessity but rather a metabolic choice that maximizes PR function and adaptability to nutrient stress conditions. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Alteration of rod and cone function in children with Usher syndrome.

PubMed

Malm, Eva; Ponjavic, Vesna; Möller, Claes; Kimberling, William J; Stone, Edwin S; Andréasson, Sten

2011-01-01

To evaluate the retinal function, with emphasis on phenotype and rate of progression, in infants and children with different genotypes of Usher syndrome. Fourteen children (2-10 years of age) with retinitis pigmentosa and hearing impairment were examined with full-field electroretinography (ERG) during general anesthesia, ophthalmologic examination, and genetic analysis. Five children were repeatedly examined (follow-up 5-10 years) with full-field ERG under local anesthesia and in 2 children multifocal ERG and optical coherence tomography (OCT) were performed. These results were compared to full-field ERG data from 58 children without retinal eye disorder. Six children were genotyped as Usher 1B, 2A, and 3A. Full-field ERG demonstrated early alterations corresponding to a rod-cone dystrophy in all children. A remaining rod function could be verified in the majority of the children up to 4 years of age. After 4 years of age, there was a further deterioration of the rod function; the progress was severe in Usher types 1 and 2 and moderate in Usher type 3. In all children, the cone function was moderately reduced, in a few cases almost normal. The results from the 58 children without retinal disorder confirm that full-field ERG during general anesthesia is reliable. Multifocal ERG confirmed a preserved central cone function and in OCT there were discrete structural alterations. Full-field ERG during general anesthesia in children with Usher syndrome demonstrates variable phenotypes and different degrees in rate of progression during childhood.

Assessment of Rod, Cone, and Intrinsically Photosensitive Retinal Ganglion Cell Contributions to the Canine Chromatic Pupillary Response.

PubMed

Yeh, Connie Y; Koehl, Kristin L; Harman, Christine D; Iwabe, Simone; Guzman, José M; Petersen-Jones, Simon M; Kardon, Randy H; Komáromy, András M

2017-01-01

The purpose of this study was to evaluate a chromatic pupillometry protocol for specific functional assessment of rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs) in dogs. Chromatic pupillometry was tested and compared in 37 dogs in different stages of primary loss of rod, cone, and combined rod/cone and optic nerve function, and in 5 wild-type (WT) dogs. Eyes were stimulated with 1-s flashes of dim (1 cd/m2) and bright (400 cd/m2) blue light (for scotopic conditions) or bright red (400 cd/m2) light with 25-cd/m2 blue background (for photopic conditions). Canine retinal melanopsin/Opn4 was cloned, and its expression was evaluated using real-time quantitative reverse transcription-PCR and immunohistochemistry. Mean ± SD percentage of pupil constriction amplitudes induced by scotopic dim blue (scDB), scotopic bright blue (scBB), and photopic bright red (phBR) lights in WT dogs were 21.3% ± 10.6%, 50.0% ± 17.5%, and 19.4% ± 7.4%, respectively. Melanopsin-mediated responses to scBB persisted for several minutes (7.7 ± 4.6 min) after stimulus offset. In dogs with inherited retinal degeneration, loss of rod function resulted in absent scDB responses, followed by decreased phBR responses with disease progression and loss of cone function. Primary loss of cone function abolished phBR responses but preserved those responses to blue light (scDB and scBB). Although melanopsin/Opn4 expression was diminished with retinal degeneration, melanopsin-expressing ipRGCs were identified for the first time in both WT and degenerated canine retinas. Pupil responses elicited by light stimuli of different colors and intensities allowed differential functional assessment of canine rods, cones, and ipRGCs. Chromatic pupillometry offers an effective tool for diagnosing retinal and optic nerve diseases.

The effects of L-glutamate, AMPA, quisqualate, and kainate on retinal horizontal cells depend on adaptational state: implications for rod-cone interactions.

PubMed

Krizaj, D; Akopian, A; Witkovsky, P

1994-09-01

transmitter, glutamate. In photopic and mesopic states the dominant cone input tonically inhibits rod to L-HC communication. This inhibition appears to occur at the postsynaptic membrane and may be mediated by second messengers.

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa.

PubMed

Beltran, William A; Cideciyan, Artur V; Lewin, Alfred S; Iwabe, Simone; Khanna, Hemant; Sumaroka, Alexander; Chiodo, Vince A; Fajardo, Diego S; Román, Alejandro J; Deng, Wen-Tao; Swider, Malgorzata; Alemán, Tomas S; Boye, Sanford L; Genini, Sem; Swaroop, Anand; Hauswirth, William W; Jacobson, Samuel G; Aguirre, Gustavo D

2012-02-07

Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment.

Effect of 11-Cis 13-Demethylretinal on Phototransduction in Bleach-Adapted Rod and Cone Photoreceptors

PubMed Central

Corson, D.Wesley; Kefalov, Vladimir J.; Cornwall, M. Carter; Crouch, Rosalie K.

2000-01-01

We used 11-cis 13-demethylretinal to examine the physiological consequences of retinal's noncovalent interaction with opsin in intact rod and cone photoreceptors during visual pigment regeneration. 11-Cis 13-demethylretinal is an analog of 11-cis retinal in which the 13 position methyl group has been removed. Biochemical experiments have shown that it is capable of binding in the chromophore pocket of opsin, forming a Schiff-base linkage with the protein to produce a pigment, but at a much slower rate than the native 11-cis retinal (Nelson, R., J. Kim deReil, and A. Kropf. 1970. Proc. Nat. Acad. Sci. USA. 66:531–538). Experimentally, this slow rate of pigment formation should allow separate physiological examination of the effects of the initial binding of retinal in the pocket and the subsequent formation of the protonated Schiff-base linkage. Currents from solitary rods and cones from the tiger salamander were recorded in darkness before and after bleaching and then after exposure to 11-cis 13-demethylretinal. In bleach-adapted rods, 11-cis 13-demethylretinal caused transient activation of phototransduction, as evidenced by a decrease of the dark current and sensitivity, acceleration of the dim flash responses, and activation of cGMP phosphodiesterase and guanylyl cyclase. The steady state of phototransduction activity was still higher than that of the bleach-adapted rod. In contrast, exposure of bleach-adapted cones to 11-cis 13-demethylretinal resulted in an immediate deactivation of transduction as measured by the same parameters. These results extend the validity of a model for the effects of the noncovalent binding of a retinoid in the chromophore pockets of rod and cone opsins to analogs capable of forming a Schiff-base and imply that the noncovalent binding by itself may play a role for the dark adaptation of photoreceptors. PMID:10919871

Partial preservation of rod and cone ERG function following subretinal injection of ARPE-19 cells in RCS rats.

PubMed

Sauvé, Y; Pinilla, I; Lund, R D

2006-04-01

We quantified rod- and cone-related electroretinogram (ERG) responses following subretinal injections of the human-derived retinal pigment epithelial (hRPE) cell line ARPE-19 at age P23 to prevent progressive photoreceptor loss in the Royal College of Surgeons (RCS) rat. Culture medium-injected eyes served as sham controls. At P60, in comparison with sham-injected eyes, all recordings from hRPE-injected eyes showed preserved scotopic a- and b-waves, oscillatory potentials, double-flash-derived rod b-waves and photopic cone b-waves, and flicker critical fusion frequencies and amplitudes. Although the actual preservation did not exceed 10% of a-wave and 20% of b-wave amplitude values in non-dystrophic RCS and deteriorated rapidly by P90, rod- and cone-related ERG parameters were still recordable up to P120 unlike the virtually unresponsive sham-injected eyes.

Variation in rod and cone density from the fovea to the mid-periphery in healthy human retinas using adaptive optics scanning laser ophthalmoscopy

PubMed Central

Wells-Gray, E M; Choi, S S; Bries, A; Doble, N

2016-01-01

Purpose To characterize the rod and cone photoreceptor mosaic at retinal locations spanning the central 60° in vivo using adaptive optics scanning laser ophthalmoscopy (AO-SLO) in healthy human eyes. Methods AO-SLO images (0.7 × 0.9°) were acquired at 680 nm from 14 locations from 30° nasal retina (NR) to 30° temporal retina (TR) in 5 subjects. Registered averaged images were used to measure rod and cone density and spacing within 60 × 60 μm regions of interest. Voronoi analysis was performed to examine packing geometry at all locations. Results Average peak cone density near the fovea was 164 000±24 000 cones/mm2 and decreased to 6700±1500 and 5400±700 cones/mm2 at 30° NR and 30° TR, respectively. Cone-to-cone spacing increased from 2.7±0.2 μm at the fovea to 14.6±1.4 μm at 30° NR and 16.3±0.7 μm at 30° TR. Rod density peaked at 25° NR (124 000±20 000 rods/mm2) and 20° TR (120 000±12 000 rods/mm2) and decreased at higher eccentricities. Center-to-center rod spacing was lowest nasally at 25° (2.1±0.1 μm). Temporally, rod spacing was lowest at 20° (2.2±0.1 μm) before increasing to 2.3±0.1 μm at 30° TR. Conclusions Both rod and cone densities showed good agreement with histology and prior AO-SLO studies. The results demonstrate the ability to image at higher retinal eccentricities than reported previously. This has clinical importance in diseases that initially affect the peripheral retina such as retinitis pigmentosa. PMID:27229708

Group III metabotropic glutamate receptors and exocytosed protons inhibit L-type calcium currents in cones but not in rods.

PubMed

Hosoi, Nobutake; Arai, Itaru; Tachibana, Masao

2005-04-20

Light responses of photoreceptors (rods and cones) are transmitted to the second-order neurons (bipolar cells and horizontal cells) via glutamatergic synapses located in the outer plexiform layer of the retina. Although it has been well established that postsynaptic group III metabotropic glutamate receptors (mGluRs) of ON bipolar cells contribute to generating the ON signal, presynaptic roles of group III mGluRs remain to be elucidated at this synaptic connection. We addressed this issue by applying the slice patch-clamp technique to the newt retina. OFF bipolar cells and horizontal cells generate a steady inward current in the dark and a transient inward current at light offset, both of which are mediated via postsynaptic non-NMDA receptors. A group III mGluR-specific agonist, L-2-amino-4-phosphonobutyric acid (L-AP-4), inhibited both the steady and off-transient inward currents but did not affect the glutamate-induced current in these postsynaptic neurons. L-AP-4 inhibited the presynaptic L-type calcium current (ICa) in cones by shifting the voltage dependence of activation to more positive membrane potentials. The inhibition of ICa was most prominent around the physiological range of cone membrane potentials. In contrast, L-AP-4 did not affect L-type ICa in rods. Paired recordings from photoreceptors and the synaptically connected second-order neurons confirmed that L-AP-4 inhibited both ICa and glutamate release in cones but not in rods. Furthermore, we found that exocytosed protons also inhibited ICa in cones but not in rods. Selective modulation of ICa in cones may help broaden the dynamic range of synaptic transfer by controlling the amount of transmitter release from cones.

Cone arrestin confers cone vision of high temporal resolution in zebrafish larvae.

PubMed

Renninger, Sabine L; Gesemann, Matthias; Neuhauss, Stephan C F

2011-02-01

Vision of high temporal resolution depends on careful regulation of photoresponse kinetics, beginning with the lifetime of activated photopigment. The activity of rhodopsin is quenched by high-affinity binding of arrestin to photoexcited phosphorylated photopigment, which effectively terminates the visual transduction cascade. This regulation mechanism is well established for rod photoreceptors, yet its role for cone vision is still controversial. In this study we therefore analyzed arrestin function in the cone-dominated vision of larval zebrafish. For both rod (arrS ) and cone (arr3 ) arrestin we isolated two paralogs, each expressed in the respective subset of photoreceptors. Labeling with paralog-specific antibodies revealed subfunctionalized expression of Arr3a in M- and L-cones, and Arr3b in S- and UV-cones. The inactivation of arr3a by morpholino knockdown technology resulted in a severe delay in photoresponse recovery which, under bright light conditions, was rate-limiting. Comparison to opsin phosphorylation-deficient animals confirmed the role of cone arrestin in late cone response recovery. Arr3a activity partially overlapped with the function of the cone-specific kinase Grk7a involved in initial response recovery. Behavioral measurements further revealed Arr3a deficiency to be sufficient to reduce temporal contrast sensitivity, providing evidence for the importance of arrestin in cone vision of high temporal resolution. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Grating acuity at different luminances in wild-type mice and in mice lacking rod or cone function.

PubMed

Schmucker, Christine; Seeliger, Mathias; Humphries, Pete; Biel, Martin; Schaeffel, Frank

2005-01-01

The mouse eye has become an important model in vision research. However, it is not known how visual acuity changes with luminance. Therefore, grating acuity of mice was measured at different luminances in an automated optomotor paradigm. Furthermore, mutant mice lacking either rods (RHO-/- and CNGB1-/-) or cones (CNGA3-/-), or both, were studied to determine the rod and cone contribution to visual acuity. Freely ranging individual mice were automatically tracked at a 25-Hz sampling rate with a self-programmed video system in a large rotating optomotor drum. The drum had a square-wave grating inside with adjustable spatial frequency. The angular speed of the mice with respect to the center of the drum and the angular orientation of the snout-tail body axis were analyzed. In addition, the motor activity of the wild-type mice was recorded at different luminances. The optomotor drum provided reliable data on visual input to the mouse's behavior and was convenient to use, since the experimenter's had only to place the mice individually in a Perspex cylinder. Optomotor grating acuity of the wild-type mice was limited to 0.3 to 0.4 cyc/deg. Maximum optomotor responses were obtained at 0.1 to 0.2 cyc/deg. The importance of visual input declined monotonically with decreasing luminance (30 cd/m2, 100%; 0.1 cd/m2, 76.4%; 0.005 cd/m2, 45.9%; and darkness, -9%). Mice lacking functional rods were able to resolve gratings up to 0.1 cyc/deg at 30 cd/m2. Surprisingly, mice lacking functional cones had an optomotor acuity that was similar to the wild-type. Double-knockout mice without rods and cones had no detectable grating acuity. Because the visual system of the mouse is more responsive at bright luminances, experiments in which visual input is important should be performed in photopic conditions (30 cd/m2 or even more). Apparently, spatial vision is governed by the rod system, which is not saturated in the mesopic or low photopic range. Mice lacking both rods and cones have no

RPGR-Associated Retinal Degeneration in Human X-Linked RP and a Murine Model

PubMed Central

Huang, Wei Chieh; Wright, Alan F.; Roman, Alejandro J.; Cideciyan, Artur V.; Manson, Forbes D.; Gewaily, Dina Y.; Schwartz, Sharon B.; Sadigh, Sam; Limberis, Maria P.; Bell, Peter; Wilson, James M.; Swaroop, Anand; Jacobson, Samuel G.

2012-01-01

Purpose. We investigated the retinal disease due to mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene in human patients and in an Rpgr conditional knockout (cko) mouse model. Methods. XLRP patients with RPGR-ORF15 mutations (n = 35, ages at first visit 5–72 years) had clinical examinations, and rod and cone perimetry. Rpgr-cko mice, in which the proximal promoter and first exon were deleted ubiquitously, were back-crossed onto a BALB/c background, and studied with optical coherence tomography and electroretinography (ERG). Retinal histopathology was performed on a subset. Results. Different patterns of rod and cone dysfunction were present in patients. Frequently, there were midperipheral losses with residual rod and cone function in central and peripheral retina. Longitudinal data indicated that central rod loss preceded peripheral rod losses. Central cone-only vision with no peripheral function was a late stage. Less commonly, patients had central rod and cone dysfunction, but preserved, albeit abnormal, midperipheral rod and cone vision. Rpgr-cko mice had progressive retinal degeneration detectable in the first months of life. ERGs indicated relatively equal rod and cone disease. At late stages, there was greater inferior versus superior retinal degeneration. Conclusions. RPGR mutations lead to progressive loss of rod and cone vision, but show different patterns of residual photoreceptor disease expression. Knowledge of the patterns should guide treatment strategies. Rpgr-cko mice had onset of degeneration at relatively young ages and progressive photoreceptor disease. The natural history in this model will permit preclinical proof-of-concept studies to be designed and such studies should advance progress toward human therapy. PMID:22807293

Mathematical Model of the Role of RdCVF in the Coexistence of Rods and Cones in a Healthy Eye.

PubMed

Camacho, Erika T; Léveillard, Thierry; Sahel, José-Alain; Wirkus, Stephen

2016-07-01

Understanding the essential components and processes for coexistence of rods and cones is at the forefront of retinal research. The recent discovery on RdCVF's mechanism and mode of action for enhancing cone survival brings us a step closer to unraveling key questions of coexistence and codependence of these neurons. In this work, we build from ecological and enzyme kinetic work on functional response kinetics and present a mathematical model that allows us to investigate the role of RdCVF and its contribution to glucose intake. Our model results and analysis predict a dual role of RdCVF for enhancing and repressing the healthy coexistence of the rods and cones. Our results show that maintaining RdCVF above a threshold value allows for coexistence. However, a significant increase above this value threatens the existence of rods as the cones become extremely efficient at uptaking glucose and begin to take most of it for themselves. We investigate the role of natural glucose intake and that due to RdCVF in both high and low nutrient levels. Our analysis reveals that under low nutrient levels coexistence is not possible regardless of the amount of RdCVF present. With high nutrient levels coexistence can be achieved with a relative small increase in glucose uptake. By understanding the contributions of rods to cones survival via RdCVF in a non-diseased retina, we hope to shed light on degenerative diseases such as retinitis pigmentosa.

Refinement of the cone-rod retinal dystrophy locus on chromosome 19q

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gregory, C.Y.; Evans, K.; Bhattacharya, S.S.

1994-11-01

Cone-rod dystrophy (CRD) is a severe example of an inherited retinal dystrophy: ophthalmic diseases that as a group constitute the commonest causes of blindness in children in the developed world and account for a significant proportion of visual handicap in adults. Two case reports suggested loci for CRD-causing genes on chromosomes 18q and chromosome 17q. Recently, we reported the results of a total genome search that localized an autosomal dominant form of CRD to chromosome 19q in the region 19q13.1-q13.2. Since then, using data from a short tandem repeat-polymorphism linkage map of chromosome 19 and recently developed microsatellite markers inmore » this region, we have been able to further refine the localization of the chromosome 19q CRD-causing gene. Seven new microsatellite markers were used to genotype 34 affected subjects, 22 unaffected subjects, and 15 spouses. Two-point, multipoint, and FASTMAP analyses were performed. 11 refs., 1 tab.« less

Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy.

PubMed

Yamamoto, Guilherme L; Baratela, Wagner A R; Almeida, Tatiana F; Lazar, Monize; Afonso, Clara L; Oyamada, Maria K; Suzuki, Lisa; Oliveira, Luiz A N; Ramos, Ester S; Kim, Chong A; Passos-Bueno, Maria Rita; Bertola, Débora R

2014-01-02

Spondylometaphyseal dysplasia with cone-rod dystrophy is a rare autosomal-recessive disorder characterized by severe short stature, progressive lower-limb bowing, flattened vertebral bodies, metaphyseal involvement, and visual impairment caused by cone-rod dystrophy. Whole-exome sequencing of four individuals affected by this disorder from two Brazilian families identified two previously unreported homozygous mutations in PCYT1A. This gene encodes the alpha isoform of the phosphate cytidylyltransferase 1 choline enzyme, which is responsible for converting phosphocholine into cytidine diphosphate-choline, a key intermediate step in the phosphatidylcholine biosynthesis pathway. A different enzymatic defect in this pathway has been previously associated with a muscular dystrophy with mitochondrial structural abnormalities that does not have cartilage and/or bone or retinal involvement. Thus, the deregulation of the phosphatidylcholine pathway may play a role in multiple genetic diseases in humans, and further studies are necessary to uncover its precise pathogenic mechanisms and the entirety of its phenotypic spectrum. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Longitudinal assessment of retinal structure and function reveals a rod-cone degeneration in a guinea pig model initially presented as night blind.

PubMed

Racine, Julie; Joly, Sandrine; Lachapelle, Pierre

2011-08-01

We have previously reported a naturally occurring retinopathy in a population of guinea pigs, where the affected animals presented a defect of the rod-mediated vision. The purpose of this study was to investigate if the mutants were affected with a stationary or degenerative retinopathy and to identify the cellular origin of this unique disorder. Electroretinogram (ERG) [postnatal day 1 (P1) to P450], light (LM) and electron microscopy (EM) [P5, P150, P450], and immunohistochemistry [P30, P150, P450] were evaluated from normal and mutant animals. Irrespective of age, the scotopic ERGs of mutants could only be evoked by bright flashes, and the resulting ERGs were of photopic waveform. Interestingly, the amplitude of the cone and the rod/cone a-waves was always of smaller amplitude in mutants, but this difference tended to decrease with age. In contrast, the b-waves were of larger amplitude than normal in photopic ERGs obtained prior to age 25 (days) and prior to age 10 for rod/cone ERGs. LM revealed, in mutants, an absence of the outer segment layer (OSL) with a reduction in the outer nuclear layer (ONL) thickness. EM disclosed the presence of cone outer segment (OS) while no rod OS could be evidenced. Immunohistochemistry revealed the presence of rhodopsin, both cone opsins as well as normal synaptophysin immunoreactivity. Finally, neither the retinal structure nor the function in the mutants achieved normal development. Results suggest that mutant animals are suffering from a degenerative retinal disorder that affects the structure and function of rods and cones.

Multiple rod–cone and cone–rod photoreceptor transmutations in snakes: Evidence from visual opsin gene expression

USGS Publications Warehouse

Simoe, Bruno F; Sampaio, Filipa L.; Loew, Ellis R.; Sanders, Kate L.; Fisher, Robert N.; Hart, Nathan S.; Hunt, David M.; Partridge, Julian C.; Gower, David J.

2016-01-01

In 1934, Gordon Walls forwarded his radical theory of retinal photoreceptor ‘transmutation’. This proposed that rods and cones used for scotopic and photopic vision, respectively, were not fixed but could evolve into each other via a series of morphologically distinguishable intermediates. Walls' prime evidence came from series of diurnal and nocturnal geckos and snakes that appeared to have pure-cone or pure-rod retinas (in forms that Walls believed evolved from ancestors with the reverse complement) or which possessed intermediate photoreceptor cells. Walls was limited in testing his theory because the precise identity of visual pigments present in photoreceptors was then unknown. Subsequent molecular research has hitherto neglected this topic but presents new opportunities. We identify three visual opsin genes, rh1, sws1 and lws, in retinal mRNA of an ecologically and taxonomically diverse sample of snakes central to Walls' theory. We conclude that photoreceptors with superficially rod- or cone-like morphology are not limited to containing scotopic or photopic opsins, respectively. Walls' theory is essentially correct, and more research is needed to identify the patterns, processes and functional implications of transmutation. Future research will help to clarify the fundamental properties and physiology of photoreceptors adapted to function in different light levels.

Multiple rod–cone and cone–rod photoreceptor transmutations in snakes: evidence from visual opsin gene expression

PubMed Central

Sampaio, Filipa L.; Loew, Ellis R.; Sanders, Kate L.; Fisher, Robert N.; Hart, Nathan S.; Hunt, David M.; Partridge, Julian C.

2016-01-01

In 1934, Gordon Walls forwarded his radical theory of retinal photoreceptor ‘transmutation’. This proposed that rods and cones used for scotopic and photopic vision, respectively, were not fixed but could evolve into each other via a series of morphologically distinguishable intermediates. Walls' prime evidence came from series of diurnal and nocturnal geckos and snakes that appeared to have pure-cone or pure-rod retinas (in forms that Walls believed evolved from ancestors with the reverse complement) or which possessed intermediate photoreceptor cells. Walls was limited in testing his theory because the precise identity of visual pigments present in photoreceptors was then unknown. Subsequent molecular research has hitherto neglected this topic but presents new opportunities. We identify three visual opsin genes, rh1, sws1 and lws, in retinal mRNA of an ecologically and taxonomically diverse sample of snakes central to Walls' theory. We conclude that photoreceptors with superficially rod- or cone-like morphology are not limited to containing scotopic or photopic opsins, respectively. Walls' theory is essentially correct, and more research is needed to identify the patterns, processes and functional implications of transmutation. Future research will help to clarify the fundamental properties and physiology of photoreceptors adapted to function in different light levels. PMID:26817768

Visual function in patients with cone-rod dystrophy (CRD) associated with mutations in the ABCA4(ABCR) gene.

PubMed

Birch, D G; Peters, A Y; Locke, K L; Spencer, R; Megarity, C F; Travis, G H

2001-12-01

Mutations in the ABCA4(ABCR) gene cause autosomal recessive Stargardt disease (STGD). ABCR mutations were identified in patients with cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) by direct sequencing of all 50 exons in 40 patients. Of 10 patients with RP, one contained two ABCR mutations suggesting a compound heterozygote. This patient had a characteristic fundus appearance with attenuated vessels, pale disks and bone-spicule pigmentation. Rod electroretinograms (ERGs) were non-detectable, cone ERGs were greatly reduced in amplitude and delayed in implicit time, and visual fields were constricted to 10 degrees diameter. Eleven of 30 (37%) patients with CRD had mutations in ABCR. In general, these patients showed reduced but detectable rod ERG responses, reduced and delayed cone responses, and poor visual acuity. Rod photoresponses to high intensity flashes were of reduced maximum amplitude but showed normal values for the gain of phototransduction. Most CRD patients with mutations in ABCR showed delayed recovery of sensitivity (dark adaptation) following exposure to bright light. Pupils were also significantly smaller in these patients compared to controls at 30 min following light exposure, consistent with a persistent 'equivalent light' background due to the accumulation of a tentatively identified 'noisy' photoproduct. Copyright 2001 Academic Press.

Null mutation in the rhodopsin kinase gene slows recovery kinetics of rod and cone phototransduction in man

PubMed Central

Cideciyan, Artur V.; Zhao, Xinyu; Nielsen, Lori; Khani, Shahrokh C.; Jacobson, Samuel G.; Palczewski, Krzysztof

1998-01-01

Rhodopsin kinase (RK), a specialized G-protein-coupled receptor kinase expressed in retina, is involved in quenching of light-induced signal transduction in photoreceptors. The role of RK in recovery after photoactivation has been explored in vitro and in vivo experimentally but has not been specifically defined in humans. We investigated the effects on human vision of a mutation in the RK gene causing Oguchi disease, a recessively inherited retinopathy. In vitro experiments demonstrated that the mutation, a deletion of exon 5, abolishes the enzymatic activity of RK and is likely a null. Both a homozygote and heterozygote with this RK mutation had recovery phase abnormalities of rod-isolated photoresponses by electroretinography (ERG); photoactivation was normal. Kinetics of rod bleaching adaptation by psychophysics were dramatically slowed in the homozygote but normal final thresholds were attained. Light adaptation was normal at low backgrounds but became abnormal at higher backgrounds. A slight slowing of cone deactivation kinetics in the homozygote was detected by ERG. Cone bleaching adaptation and background adaptation were normal. In this human in vivo condition without a functional RK and probable lack of phosphorylation and arrestin binding to activated rhodopsin, reduction of photolyzed chromophore and regeneration processes with 11-cis-retinal probably constitute the sole pathway for recovery of rod sensitivity. The role of RK in rods would thus be to accelerate inactivation of activated rhodopsin molecules that in concert with regeneration leads to the normal rate of recovery of sensitivity. Cones may rely mainly on regeneration for the inactivation of photolyzed visual pigment, but RK also contributes to cone recovery. PMID:9419375

Evaluation of the X-Linked High-Grade Myopia Locus (MYP1) with Cone Dysfunction and Color Vision Deficiencies

PubMed Central

Metlapally, Ravikanth; Michaelides, Michel; Bulusu, Anuradha; Li, Yi-Ju; Schwartz, Marianne; Rosenberg, Thomas; Hunt, David M.; Moore, Anthony T.; Züchner, Stephan; Rickman, Catherine Bowes; Young, Terri L.

2014-01-01

Purpose X-linked high myopia with mild cone dysfunction and color vision defects has been mapped to chromosome Xq28 (MYP1 locus). CXorf2/TEX28 is a nested, intercalated gene within the red-green opsin cone pigment gene tandem array on Xq28. The authors investigated whether TEX28 gene alterations were associated with the Xq28-linked myopia phenotype. Genomic DNA from five pedigrees (with high myopia and either protanopia or deuteranopia) that mapped to Xq28 were screened for TEX28 copy number variations (CNVs) and sequence variants. Methods To examine for CNVs, ultra-high resolution array-comparative genomic hybridization (array-CGH) assays were performed comparing the subject genomic DNA with control samples (two pairs from two pedigrees). Opsin or TEX28 gene-targeted quantitative real-time gene expression assays (comparative CT method) were performed to validate the array-CGH findings. All exons of TEX28, including intron/exon boundaries, were amplified and sequenced using standard techniques. Results Array-CGH findings revealed predicted duplications in affected patient samples. Although only three copies of TEX28 were previously reported within the opsin array, quantitative real-time analysis of the TEX28 targeted assay of affected male or carrier female individuals in these pedigrees revealed either fewer (one) or more (four or five) copies than did related and control unaffected individuals. Sequence analysis of TEX28 did not reveal any variants associated with the disease status. Conclusions CNVs have been proposed to play a role in disease inheritance and susceptibility as they affect gene dosage. TEX28 gene CNVs appear to be associated with the MYP1 X-linked myopia phenotypes. PMID:19098318

The Crystal Structure of GCAP3 Suggests Molecular Mechanism of GCAP–linked Cone Dystrophies

PubMed Central

Stephen, Ricardo; Palczewski, Krzysztof; Sousa, Marcelo C.

2014-01-01

Summary Absorption of light by visual pigments initiates the phototransduction pathway that results in degradation of the intracellular pool of cyclic–GMP (cGMP). This hydrolysis promotes the closing of cGMP–gated cation channels and consequent hyperpolarization of rod and cone photoreceptor cell membranes. Guanylate Cyclase Activating Proteins (GCAPs) are a family of proteins that regulate retinal guanylate cyclase (GC) activity in a Ca2+–dependent manner. At high [Ca2+], typical of the dark–adapted state (~500 nM), GCAPs inhibit retinal GCs. At the low [Ca2+] (~50 nM) that occur after the closing of cGMP-gated channels, GCAPs activate retinal GCs to replenish dark–state cGMP levels. Here, we report the crystal structure of unmyristoylated human GCAP3 with Ca2+ bound. GCAP3 is an EF–hand Ca2+–binding protein with Ca2+ bound to EF2, 3 and 4, while Ca2+ binding to EF–hand 1 is disabled. GCAP3 contains two domains with the EF–hand motifs arranged in a tandem array similar to GCAP2 and members of the recoverin subfamily of Ca2+–binding proteins. Residues not involved in Ca2+ binding, but conserved in all GCAPs, cluster around EF1 in the N–terminal domain and may represent the interface with GCs. Five point mutations in the closely related GCAP1 have been linked to the etiology of cone dystrophies. These residues are conserved in GCAP3 and the structure suggests important roles for these amino acids. We present a homology model of GCAP1 based on GCAP3 that offers insight into the molecular mechanism underlying the autosomal dominant cone dystrophies produced by GCAP1 mutations. PMID:16626734

The crystal structure of GCAP3 suggests molecular mechanism of GCAP-linked cone dystrophies.

PubMed

Stephen, Ricardo; Palczewski, Krzysztof; Sousa, Marcelo C

2006-06-02

Absorption of light by visual pigments initiates the phototransduction pathway that results in degradation of the intracellular pool of cyclic-GMP (cGMP). This hydrolysis promotes the closing of cGMP-gated cation channels and consequent hyperpolarization of rod and cone photoreceptor cell membranes. Guanylate cyclase-activating proteins (GCAPs) are a family of proteins that regulate retinal guanylate cyclase (GC) activity in a Ca2+-dependent manner. At high [Ca2+], typical of the dark-adapted state (approximately 500 nM), GCAPs inhibit retinal GCs. At the low [Ca2+] (approximately 50 nM) that occurs after the closing of cGMP-gated channels, GCAPs activate retinal GCs to replenish dark-state cGMP levels. Here, we report the crystal structure of unmyristoylated human GCAP3 with Ca2+ bound. GCAP3 is an EF-hand Ca2+-binding protein with Ca2+ bound to EF2, 3 and 4, while Ca2+ binding to EF-hand 1 is disabled. GCAP3 contains two domains with the EF-hand motifs arranged in a tandem array similar to GCAP2 and members of the recoverin subfamily of Ca2+-binding proteins. Residues not involved in Ca2+ binding, but conserved in all GCAPs, cluster around EF1 in the N-terminal domain and may represent the interface with GCs. Five point mutations in the closely related GCAP1 have been linked to the etiology of cone dystrophies. These residues are conserved in GCAP3 and the structure suggests important roles for these amino acids. We present a homology model of GCAP1 based on GCAP3 that offers insight into the molecular mechanism underlying the autosomal dominant cone dystrophies produced by GCAP1 mutations.

Ectopic expression of cone-specific G-protein-coupled receptor kinase GRK7 in zebrafish rods leads to lower photosensitivity and altered responses

PubMed Central

Vogalis, F; Shiraki, T; Kojima, D; Wada, Y; Nishiwaki, Y; Jarvinen, J L P; Sugiyama, J; Kawakami, K; Masai, I; Kawamura, S; Fukada, Y; Lamb, T D

2011-01-01

Abstract To investigate the roles of G-protein receptor kinases (GRKs) in the light responses of vertebrate photoreceptors, we generated transgenic zebrafish lines, the rods of which express either cone GRK (GRK7) or rod GRK (GRK1) in addition to the endogenous GRK1, and we then measured the electrophysiological characteristics of single-cell responses and the behavioural responses of intact animals. Our study establishes the zebrafish expression system as a convenient platform for the investigation of specific components of the phototransduction cascade. The addition of GRK1 led to minor changes in rod responses. However, exogenous GRK7 in GRK7-tg animals led to lowered rod sensitivity, as occurs in cones, but surprisingly to slower response kinetics. Examination of responses to long series of very dim flashes suggested the possibility that the GRK7-tg rods generated two classes of single-photon response, perhaps corresponding to the interaction of activated rhodopsin with GRK1 (giving a standard response) or with GRK7 (giving a very small response). Behavioural measurement of optokinetic responses (OKR) in intact GRK7-tg zebrafish larvae showed that the overall rod visual pathway was less sensitive, in accord with the lowered sensitivity of the rods. These results help provide an understanding for the molecular basis of the electrophysiological differences between cones and rods. PMID:21486791

Photoreceptor Cell Death, Proliferation and Formation of Hybrid Rod/S-Cone Photoreceptors in the Degenerating STK38L Mutant Retina

PubMed Central

Berta, Ágnes I.; Boesze-Battaglia, Kathleen; Genini, Sem; Goldstein, Orly; O'Brien, Paul J.; Szél, Ágoston; Acland, Gregory M.; Beltran, William A.; Aguirre, Gustavo D.

2011-01-01

A homozygous mutation in STK38L in dogs impairs the late phase of photoreceptor development, and is followed by photoreceptor cell death (TUNEL) and proliferation (PCNA, PHH3) events that occur independently in different cells between 7–14 weeks of age. During this period, the outer nuclear layer (ONL) cell number is unchanged. The dividing cells are of photoreceptor origin, have rod opsin labeling, and do not label with markers specific for macrophages/microglia (CD18) or Müller cells (glutamine synthetase, PAX6). Nestin labeling is absent from the ONL although it labels the peripheral retina and ciliary marginal zone equally in normals and mutants. Cell proliferation is associated with increased cyclin A1 and LATS1 mRNA expression, but CRX protein expression is unchanged. Coincident with photoreceptor proliferation is a change in the photoreceptor population. Prior to cell death the photoreceptor mosaic is composed of L/M- and S-cones, and rods. After proliferation, both cone types remain, but the majority of rods are now hybrid photoreceptors that express rod opsin and, to a lesser extent, cone S-opsin, and lack NR2E3 expression. The hybrid photoreceptors renew their outer segments diffusely, a characteristic of cones. The results indicate the capacity for terminally differentiated, albeit mutant, photoreceptors to divide with mutations in this novel retinal degeneration gene. PMID:21980341

Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations.

PubMed

Beltran, William A; Cideciyan, Artur V; Boye, Shannon E; Ye, Guo-Jie; Iwabe, Simone; Dufour, Valerie L; Marinho, Luis Felipe; Swider, Malgorzata; Kosyk, Mychajlo S; Sha, Jin; Boye, Sanford L; Peterson, James J; Witherspoon, C Douglas; Alexander, John J; Ying, Gui-Shuang; Shearman, Mark S; Chulay, Jeffrey D; Hauswirth, William W; Gamlin, Paul D; Jacobson, Samuel G; Aguirre, Gustavo D

2017-08-02

X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is an early onset and severe cause of blindness. Successful proof-of-concept studies in a canine model have recently shown that development of a corrective gene therapy for RPGR-XLRP may now be an attainable goal. In preparation for a future clinical trial, we have here optimized the therapeutic AAV vector construct by showing that GRK1 (rather than IRBP) is a more efficient promoter for targeting gene expression to both rods and cones in non-human primates. Two transgenes were used in RPGR mutant (XLPRA2) dogs under the control of the GRK1 promoter. First was the previously developed stabilized human RPGR (hRPGRstb). Second was a new full-length stabilized and codon-optimized human RPGR (hRPGRco). Long-term (>2 years) studies with an AAV2/5 vector carrying hRPGRstb under control of the GRK1 promoter showed rescue of rods and cones from degeneration and retention of vision. Shorter term (3 months) studies demonstrated comparable preservation of photoreceptors in canine eyes treated with an AAV2/5 vector carrying either transgene under the control of the GRK1 promoter. These results provide the critical molecular components (GRK1 promoter, hRPGRco transgene) to now construct a therapeutic viral vector optimized for RPGR-XLRP patients. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Targeted Ablation of the Pde6h Gene in Mice Reveals Cross-species Differences in Cone and Rod Phototransduction Protein Isoform Inventory*

PubMed Central

Brennenstuhl, Christina; Tanimoto, Naoyuki; Burkard, Markus; Wagner, Rebecca; Bolz, Sylvia; Trifunovic, Dragana; Kabagema-Bilan, Clement; Paquet-Durand, Francois; Beck, Susanne C.; Huber, Gesine; Seeliger, Mathias W.; Ruth, Peter; Wissinger, Bernd; Lukowski, Robert

2015-01-01

Phosphodiesterase-6 (PDE6) is a multisubunit enzyme that plays a key role in the visual transduction cascade in rod and cone photoreceptors. Each type of photoreceptor utilizes discrete catalytic and inhibitory PDE6 subunits to fulfill its physiological tasks, i.e. the degradation of cyclic guanosine-3′,5′-monophosphate at specifically tuned rates and kinetics. Recently, the human PDE6H gene was identified as a novel locus for autosomal recessive (incomplete) color blindness. However, the three different classes of cones were not affected to the same extent. Short wave cone function was more preserved than middle and long wave cone function indicating that some basic regulation of the PDE6 multisubunit enzyme was maintained albeit by a unknown mechanism. To study normal and disease-related functions of cone Pde6h in vivo, we generated Pde6h knock-out (Pde6h−/−) mice. Expression of PDE6H in murine eyes was restricted to both outer segments and synaptic terminals of short and long/middle cone photoreceptors, whereas Pde6h−/− retinae remained PDE6H-negative. Combined in vivo assessment of retinal morphology with histomorphological analyses revealed a normal overall integrity of the retinal organization and an unaltered distribution of the different cone photoreceptor subtypes upon Pde6h ablation. In contrast to human patients, our electroretinographic examinations of Pde6h−/− mice suggest no defects in cone/rod-driven retinal signaling and therefore preserved visual functions. To this end, we were able to demonstrate the presence of rod PDE6G in cones indicating functional substitution of PDE6. The disparities between human and murine phenotypes caused by mutant Pde6h/PDE6H suggest species-to-species differences in the vulnerability of biochemical and neurosensory pathways of the visual signal transduction system. PMID:25739440

Cone opsins, colour blindness and cone dystrophy: Genotype-phenotype correlations.

PubMed

Gardner, J C; Michaelides, M; Hardcastle, A J

2016-05-25

X-linked cone photoreceptor disorders caused by mutations in the OPN1LW (L) and OPN1MW (M) cone opsin genes on chromosome Xq28 include a range of conditions from mild stable red-green colour vision deficiencies to severe cone dystrophies causing progressive loss of vision and blindness. Advances in molecular genotyping and functional analyses of causative variants, combined with deep retinal phenotyping, are unravelling genetic mechanisms underlying the variability of cone opsin disorders.

Response to Drs. Shastry and Trese: Phenotype-genotype correlations in X-linked retinitis pigmentosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaplan, J.; Munnich, A.

1996-11-11

Shastry and Trese recently reported on a large kindred with X-linked retinitis pigmentosa (XLRP) characterized by a loss of central vision and preserved peripheral function. In their report, the disease had an early onset with severe myopia and a loss of central vision, while night blindness occurred later. Genetic analysis suggested that the disease was linked to the RP2 locus, and the authors raised the question of whether other cases linked to RP2 could display a similar loss of central vision. Three years ago, we reported on 4 large XLRP pedigrees with a very early onset with severe myopia andmore » early loss of visual acuity, while in 5 other families the disease started later with night blindness. We showed that the first clinical form was linked to RP2, while the second was linked to RP3. Thus, the major difference between the two forms concerns the initial symptom, information which can be obtained from the parents and patients after careful questioning. By contrast, in adult life, no difference in either severity of disease or aspect of the fundus was observed in our series, regardless of the clinical subtype of XLRP. Some months later, Jacobson et al. reported on a pedigree with an RP2 genotype, and their data support the notion that in XLRP of RP2 type 1, cone dysfunction takes place first, and as the disease advances both rods and cones are affected. We were very happy, therefore, to read that the study of Shastry and Trese fully confirmed our previous findings. 3 refs.« less

Abnormal Cone Structure in Foveal Schisis Cavities in X-Linked Retinoschisis from Mutations in Exon 6 of the RS1 Gene

PubMed Central

Ratnam, Kavitha; Birch, David G.; Sundquist, Sanna M.; Lucero, Anna S.; Zhang, Yuhua; Meltzer, Meira; Smaoui, Nizar; Roorda, Austin

2011-01-01

Purpose. To evaluate macular cone structure in patients with X-linked retinoschisis (XLRS) caused by mutations in exon 6 of the RS1 gene. Methods. High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT) in two patients with XLRS and 27 age-similar healthy subjects. Retinal structure was correlated with best-corrected visual acuity, kinetic and static perimetry, fundus-guided microperimetry, full-field electroretinography (ERG), and multifocal ERG. The six coding exons and the flanking intronic regions of the RS1 gene were sequenced in each patient. Results. Two unrelated males, ages 14 and 29, with visual acuity ranging from 20/32 to 20/63, had macular schisis with small relative central scotomas in each eye. The mixed scotopic ERG b-wave was reduced more than the a-wave. SD-OCT showed schisis cavities in the outer and inner nuclear and plexiform layers. Cone spacing was increased within the largest foveal schisis cavities but was normal elsewhere. In each patient, a mutation in exon 6 of the RS1 gene was identified and was predicted to change the amino acid sequence in the discoidin domain of the retinoschisin protein. Conclusions. AOSLO images of two patients with molecularly characterized XLRS revealed increased cone spacing and abnormal packing in the macula of each patient, but cone coverage and function were near normal outside the central foveal schisis cavities. Although cone density is reduced, the preservation of wave-guiding cones at the fovea and eccentric macular regions has prognostic and therapeutic implications for XLRS patients with foveal schisis. (Clinical Trials.gov number, NCT00254605.) PMID:22110067

Role of subunit assembly in autosomal dominant retinitis pigmentosa linked to mutations in peripherin 2.

PubMed

Molday, Robert S; Molday, Laurie L; Loewen, Christopher J R

2004-01-01

Peripherin 2 is a photoreceptor-specific membrane protein implicated in outer segment disk morphogenesis and linked to various retinopathies including autosomal dominant retinitis pigmentosa (ADRP). Peripherin 2 and ROM1 assemble as a mixture of core noncovalent homomeric and heteromeric tetramers that further link together through disulfide bonds to form higher order oligomers. These complexes are critical for disk rim formation and outer segment structure through interaction with the cGMP-gated channel and other photoreceptor proteins. We have examined the role of subunit assembly in peripherin 2 targeting to disks, outer segment structure, and photoreceptor degeneration by examining molecular and cellular properties of peripherin 2 mutants in COS-1 cells and transgenic Xenopus laevis rod photoreceptors. Wild-type (WT) and the ADRP-linked P216L mutant were transported and incorporated into newly formed outer segment disks of transgenic X. laevis. The P216L mutant, however, induced progressive outer segment instability and photoreceptor degeneration possibly through the introduction of a new N-linked oligosaccharide chain. In contrast, the C214S and L185P disease-linked, tetramerization-defective mutants, were retained in the inner segment, but did not affect outer segment structure or induce photoreceptor degeneration. Together, these results indicate that peripherin 2 mutations can cause ADRP either through a deficiency in WT peripherin 2 (C214S, 1.185P) or by a dominant negative effect on disk stability (P216L).

Restoration of vision in the pde6β-deficient dog, a large animal model of rod-cone dystrophy.

PubMed

Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

2012-11-01

Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment.

Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.

PubMed

Goji, Katsumi; Ozaki, Kayo; Sadewa, Ahmad H; Nishio, Hisahide; Matsuo, Masafumi

2006-02-01

Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively. The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance. We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation. Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.

Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

PubMed

Klevering, B Jeroen; Yzer, Suzanne; Rohrschneider, Klaus; Zonneveld, Marijke; Allikmets, Rando; van den Born, L Ingeborgh; Maugeri, Alessandra; Hoyng, Carel B; Cremers, Frans P M

2004-12-01

Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.

Distinct and Atypical Intrinsic and Extrinsic Cell Death Pathways between Photoreceptor Cell Types upon Specific Ablation of Ranbp2 in Cone Photoreceptors

PubMed Central

Cho, Kyoung-in; Yu, Minzhong; Hao, Ying; Qiu, Sunny; Pillai, Indulekha C. L.; Peachey, Neal S.; Ferreira, Paulo A.

2013-01-01

Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (Ranbp2), a cell context-dependent pleiotropic protein linked to neuroprotection, familial necrotic encephalopathies, acute transverse myelitis and tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of metalloproteinase 11/stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of caspase-7 without apoptosis. Conversely, PARP1+-apoptotic rods develop upon sequential activation of caspase-9 and caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct retinal spatial

The effects of rod and cone loss on the photic regulation of locomotor activity and heart rate.

PubMed

Thompson, Stewart; Lupi, Daniela; Hankins, Mark W; Peirson, Stuart N; Foster, Russell G

2008-08-01

Behavioral responses to light indirectly affect cardiovascular output, but in anesthetized rodents a direct effect of light on heart rate has also been described. Both the basis for this response and the contribution of rods, cones and melanopsin-based photosensitive retinal ganglion cells (pRGCs) remains unknown. To understand how light acutely regulates heart rate we studied responses to light in mice lacking all rod and cone photoreceptors (rd/rd cl ) along with wild-type controls. Our initial experiments delivered light to anesthetized mice at Zeitgeber time (ZT)16 (4 h after lights off, mid-activity phase) and produced an increase in heart rate in wild-type mice, but not in rd/rd cl animals. By contrast, parallel experiments in freely-moving mice demonstrated that light exposure at this time suppressed heart rate and activity in both genotypes. Because of the effects of anesthesia, all subsequent studies were conducted in freely-moving animals. The effects of light were also assessed at ZT6 (mid-rest phase). At this timepoint, wild-type mice showed an irradiance-dependent increase in heart rate and activity. By contrast, rd/rd cl mice failed to show any modulation of heart rate or activity, even at very high irradiances. Increases in heart rate preceded increases in locomotor activity and remained elevated when locomotor activity ceased, suggesting that these two responses are at least partially uncoupled. Collectively, our results show an acute and phase-dependent effect of light on cardiovascular output in mice. Surprisingly, this irradiance detection response is dependent upon rod and cone photoreceptors, with no apparent contribution from melanopsin pRGCs.

Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

PubMed Central

Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

2012-01-01

Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment. PMID:22828504

Localization to Xq22 and clinical update of a family with X-linked recessive mental retardation with progression sensorineural deafness, progressive tapeto-retinal degeneration and dystonia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tranebjaerg, L.; Schwartz, C.; Huggins, K.

1994-07-15

In a reinvestigation of a six-generation Norwegian family, originally reported with non-syndromic X-linked recessive deafness by Mohr and Mageroy, we have demonstrated several syndromic manifestations. The 10 clinically characterized affected males range in age from 14-61 years, and show progressive mental deterioration and visual disability. Ophthalmological and electrophysiological studies showed myopia, decreased visual acuity, combined cone-rod dystrophy as well as central areolar dystrophy by means of ERG. Brain CT-scans showed cortical and central atrophy without predilection to specific areas. Linkage analysis, using X-chromosomal RFLPs and CA-repeats, yielded a maximum LOD score of 4.37 with linkage to DXS17. DXS17 is localizedmore » to Xq22. One recombinant with COL4A5 (deficient in Alport syndrome) was observed. Results from the studies of this family will be important in reclassification of non-syndromic X-linked deafness since the family now represents syndromic deafness and XLMR with a specific phenotype.« less

Morphological changes in the anterior segment of the Abyssinian cat eye with hereditary rod-cone degeneration.

PubMed

May, Chr Albrecht; Lütjen-Drecoll, Elke; Narfström, Kristina

2005-10-01

The purpose of this study was to investigate morphological changes of the anterior segment of the eye in Abyssinian cats with progressive rod-cone degeneration and to correlate them with blood flow data obtained in the same animals. Sections of the left eyes of six normal cats and of eight cats with different stages of hereditary retinal degeneration were prepared for transmission and scanning electron microscopy. Tangential and sagittal sections were also stained with antibodies against substance P, tyrosine hydroxylase, panneuronal marker PGP9.5, nitric oxide synthase, synaptophysin, and smooth muscle alpha-actin. In Abyssinian cats with hereditary rod-cone degeneration, significant changes were observed in the iris consisting of irregularities in the vascular wall of smaller arteries without changes in their innervation pattern. The ciliary processes were shorter than in normal cats, and their structure appeared more compact and retracted. Slight changes were also observed in the anterior part of the ciliary epithelium. The anterior chamber angle region did not appear to be affected. Clear morphological correlations to the physiological blood flow data were observed in the anterior eye segment, pointing not only to functional but also morphological vascular abnormalities in this animal model for retinitis pigmentosa.

Highly efficient retinal metabolism in cones

PubMed Central

Miyazono, Sadaharu; Shimauchi-Matsukawa, Yoshie; Tachibanaki, Shuji; Kawamura, Satoru

2008-01-01

After bleaching of visual pigment in vertebrate photoreceptors, all-trans retinal is reduced to all-trans retinol by retinol dehydrogenases (RDHs). We investigated this reaction in purified carp rods and cones, and we found that the reducing activity toward all-trans retinal in the outer segment (OS) of cones is >30 times higher than that of rods. The high activity of RDHs was attributed to high content of RDH8 in cones. In the inner segment (IS) in both rods and cones, RDH8L2 and RDH13 were found to be the major enzymes among RDH family proteins. We further found a previously undescribed and effective pathway to convert 11-cis retinol to 11-cis retinal in cones: this oxidative conversion did not require NADP+ and instead was coupled with reduction of all-trans retinal to all-trans retinol. The activity was >50 times effective than the oxidizing activity of RDHs that require NADP+. These highly effective reactions of removal of all-trans retinal by RDH8 and production of 11-cis retinal by the coupling reaction are probably the underlying mechanisms that ensure effective visual pigment regeneration in cones that function under much brighter light conditions than rods. PMID:18836074

X-linked dominant protoporphyria: The first reported Japanese case.

PubMed

Ninomiya, Yukiko; Kokunai, Yasuhito; Tanizaki, Hideaki; Akasaka, Eijiro; Nakano, Hajime; Moriwaki, Shinichi

2016-04-01

A 12-year-old boy with photosensitivity since 3 years of age presented with small concavities on both cheeks, the nasal root and the dorsal surface of both hands. According to the clinical features, erythropoietic protoporphyria (EPP) was suspected. Urine and blood samples were tested for porphyrin derivatives, which revealed a markedly elevated level of erythrocyte protoporphyrin (EP) and a diagnosis of EPP was made. The patient's mother had no photosensitivity, however, lesions appearing slightly as small scars were found on the dorsum of her right hand; his elder sister and father showed no rash. The EP levels were elevated in samples from his mother and mildly elevated in those from his elder sister and father. To obtain a definitive diagnosis, genetic analyses were performed using samples from all family members, which revealed no mutations in the ferrochelatase-encoding gene (FECH), which is responsible for EPP. Instead, a pathological mutation of the 5-aminolevulinic acid synthase-encoding gene (ALAS2) was identified in samples from the patient, his mother and his elder sister, confirming a definitive diagnosis of X-linked dominant protoporphyria (XLDPP). This is the first Japanese family reported to have XLDPP, demonstrating evidence of the condition in Japan. In addition, because XLDPP is very similar to EPP in its clinical aspects and laboratory findings, a genetic analysis is required for the differential diagnosis. © 2015 Japanese Dermatological Association.

Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

PubMed

Klevering, B Jeroen; Blankenagel, Anita; Maugeri, Alessandra; Cremers, Frans P M; Hoyng, Carel B; Rohrschneider, Klaus

2002-06-01

To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were reviewed after molecular analysis revealed mutations in the ABCA4 gene. In two of the patients both the photopic and scotopic electroretinogram were nonrecordable. In the remainder, the photopic cone b-wave amplitudes appeared to be more seriously affected than the scotopic rod b-wave amplitudes. Although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Fundoscopy revealed evidence of early-onset maculopathy, sometimes accompanied by involvement of the retinal periphery in the later stages of the disease. Mutations in the ABCA4 gene are the pathologic cause of the CRD-like dystrophy in these patients, and the resultant clinical pictures are complex and heterogeneous. Given this wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful.

Nephrogenic diabetes insipidus: an X chromosome-linked dominant inheritance pattern with a vasopressin type 2 receptor gene that is structurally normal.

PubMed Central

Friedman, E; Bale, A E; Carson, E; Boson, W L; Nordenskjöld, M; Ritzén, M; Ferreira, P C; Jammal, A; De Marco, L

1994-01-01

Nephrogenic diabetes insipidus is a rare hereditary disorder, most commonly transmitted in an X chromosome-linked recessive manner and characterized by the lack of renal response to the action of antidiuretic hormone [Arg8]vasopressin. The vasopressin type 2 receptor (V2R) has been suggested to be the gene that causes the disease, and its role in disease pathogenesis is supported by mutations within this gene in affected individuals. Using the PCR, denaturing gradient gel electrophoresis, and direct DNA sequencing, we examined the V2R gene in four unrelated kindreds. In addition, linkage analysis with chromosome Xq28 markers was done in one large Brazilian kindred with an apparent unusual X chromosome-linked dominant inheritance pattern. In one family, a mutation in codon 280, causing a Tyr-->Cys substitution in the sixth transmembrane domain of the receptor, was found. In the other three additional families with nephrogenic diabetes insipidus, the V2R-coding region was normal in sequence. In one large Brazilian kindred displaying an unusual X chromosome-linked dominant mode of inheritance, the disease-related gene was localized to the same region of the X chromosome as the V2R, but no mutations were found, thus raising the possibility that this disease is caused by a gene other than V2R. Images PMID:8078903

℮-conome: an automated tissue counting platform of cone photoreceptors for rodent models of retinitis pigmentosa.

PubMed

Clérin, Emmanuelle; Wicker, Nicolas; Mohand-Saïd, Saddek; Poch, Olivier; Sahel, José-Alain; Léveillard, Thierry

2011-12-20

Retinitis pigmentosa is characterized by the sequential loss of rod and cone photoreceptors. The preservation of cones would prevent blindness due to their essential role in human vision. Rod-derived Cone Viability Factor is a thioredoxin-like protein that is secreted by rods and is involved in cone survival. To validate the activity of Rod-derived Cone Viability Factors (RdCVFs) as therapeutic agents for treating retinitis Pigmentosa, we have developed e-conome, an automated cell counting platform for retinal flat mounts of rodent models of cone degeneration. This automated quantification method allows for faster data analysis thereby accelerating translational research. An inverted fluorescent microscope, motorized and coupled to a CCD camera records images of cones labeled with fluorescent peanut agglutinin lectin on flat-mounted retinas. In an average of 300 fields per retina, nine Z-planes at magnification X40 are acquired after two-stage autofocus individually for each field. The projection of the stack of 9 images is subject to a threshold, filtered to exclude aberrant images based on preset variables. The cones are identified by treating the resulting image using 13 variables empirically determined. The cone density is calculated over the 300 fields. The method was validated by comparison to the conventional stereological counting. The decrease in cone density in rd1 mouse was found to be equivalent to the decrease determined by stereological counting. We also studied the spatiotemporal pattern of the degeneration of cones in the rd1 mouse and show that while the reduction in cone density starts in the central part of the retina, cone degeneration progresses at the same speed over the whole retinal surface. We finally show that for mice with an inactivation of the Nucleoredoxin-like genes Nxnl1 or Nxnl2 encoding RdCVFs, the loss of cones is more pronounced in the ventral retina. The automated platform ℮-conome used here for retinal disease is a tool that

Guanylate cyclase-activating protein 2 contributes to phototransduction and light adaptation in mouse cone photoreceptors.

PubMed

Vinberg, Frans; Peshenko, Igor V; Chen, Jeannie; Dizhoor, Alexander M; Kefalov, Vladimir J

2018-05-11

Light adaptation of photoreceptor cells is mediated by Ca 2+ -dependent mechanisms. In darkness, Ca 2+ influx through cGMP-gated channels into the outer segment of photoreceptors is balanced by Ca 2+ extrusion via Na + /Ca 2+ , K + exchangers (NCKXs). Light activates a G protein signaling cascade, which closes cGMP-gated channels and decreases Ca 2+ levels in photoreceptor outer segment because of continuing Ca 2+ extrusion by NCKXs. Guanylate cyclase-activating proteins (GCAPs) then up-regulate cGMP synthesis by activating retinal membrane guanylate cyclases (RetGCs) in low Ca 2+ This activation of RetGC accelerates photoresponse recovery and critically contributes to light adaptation of the nighttime rod and daytime cone photoreceptors. In mouse rod photoreceptors, GCAP1 and GCAP2 both contribute to the Ca 2+ -feedback mechanism. In contrast, only GCAP1 appears to modulate RetGC activity in mouse cones because evidence of GCAP2 expression in cones is lacking. Surprisingly, we found that GCAP2 is expressed in cones and can regulate light sensitivity and response kinetics as well as light adaptation of GCAP1-deficient mouse cones. Furthermore, we show that GCAP2 promotes cGMP synthesis and cGMP-gated channel opening in mouse cones exposed to low Ca 2+ Our biochemical model and experiments indicate that GCAP2 significantly contributes to the activation of RetGC1 at low Ca 2+ when GCAP1 is not present. Of note, in WT mouse cones, GCAP1 dominates the regulation of cGMP synthesis. We conclude that, under normal physiological conditions, GCAP1 dominates the regulation of cGMP synthesis in mouse cones, but if its function becomes compromised, GCAP2 contributes to the regulation of phototransduction and light adaptation of cones. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Characterisation of the canine rod-cone dysplasia type one gene (rod photoreceptor cGMP phosphodiesterase beta subunit (PDEB)) - a model for human retinitis pigmentosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clements, P.J.M.; Gregory, C.Y.; Petersen-Jones, S.M.

1994-09-01

Rod-cone dysplasia type one (rod-1) is an early onset, autosomal recessive retinal dystrophy segregating in the Irish setter breed. It is a model for certain forms of human autosomal recessive retinitis pigmentosa (arRP) caused by mutations in the same gene, PDEB. We confirmed the codon 807 Trp to Stop mutation and were the first to show cosegregation of the mutant allele with disease in a pedigree. We believe that this currently represents the best animal model available for some aspects of arRP, since canine tissues are relatively easy to access compared to human and yet the canine eye is ofmore » comparable size, unlike that of the rd mouse. This facilitates therapeutic intervention particularly at the subretinal level. In order to more fully investigate this model we have been characterizing the PDEB gene in the normal dog. Using PCR we have partially mapped the intron/exon structure, demonstrating a very high degree of evolutionary conservation with the mouse and human genes. RT-PCR has been used to reveal expression in a variety of neural and non-neural tissues. A PCR product spanning exons 19 to 22 (which also contains the site for the rcd-1 mutation) is detected in retina but also in tissues such as visual cortex, cerebral cortex, cerebellum, lateral geniculate nucleus, adrenal gland, lung, kidney and ovary. All of these tissues gave a negative result with primers for rds/peripherin, a gene which is expressed in rods and cones. This raises interesting questions about the regulation of PDEB transcripts which is initially being investigated by Northern analysis. In addition, anchored PCR techniques have generated upstream genomic sequences and we are currently mapping the 5{prime} extent of the mRNA transcript in the retina. This will facilitate the analysis of potential upstream promoter elements involved in directing expression.« less

Multi-mounted X-ray cone-beam computed tomography

NASA Astrophysics Data System (ADS)

Fu, Jian; Wang, Jingzheng; Guo, Wei; Peng, Peng

2018-04-01

As a powerful nondestructive inspection technique, X-ray computed tomography (X-CT) has been widely applied to clinical diagnosis, industrial production and cutting-edge research. Imaging efficiency is currently one of the major obstacles for the applications of X-CT. In this paper, a multi-mounted three dimensional cone-beam X-CT (MM-CBCT) method is reported. It consists of a novel multi-mounted cone-beam scanning geometry and the corresponding three dimensional statistical iterative reconstruction algorithm. The scanning geometry is the most iconic design and significantly different from the current CBCT systems. Permitting the cone-beam scanning of multiple objects simultaneously, the proposed approach has the potential to achieve an imaging efficiency orders of magnitude greater than the conventional methods. Although multiple objects can be also bundled together and scanned simultaneously by the conventional CBCT methods, it will lead to the increased penetration thickness and signal crosstalk. In contrast, MM-CBCT avoids substantially these problems. This work comprises a numerical study of the method and its experimental verification using a dataset measured with a developed MM-CBCT prototype system. This technique will provide a possible solution for the CT inspection in a large scale.

Characterization of the rod photoresponse isolated from the dark-adapted primate ERG.

PubMed

Jamison, J A; Bush, R A; Lei, B; Sieving, P A

2001-01-01

The a-wave of the human dark-adapted ERG is thought to derive from activity of rod photoreceptors. However, other sources within the retina could potentially perturb this simple equation. We investigated the extent to which the short-latency dark-adapted rod a-wave of the primate ERG is dominated by the rod photoresponse and the applicability of the phototransduction model to fit the rod a-wave. Dark-adapted Ganzfeld ERGs were elicited over a 5-log-unit intensity range using short bright xenon flashes, and the light-adapted cone responses were subtracted to isolate the rod ERG a-wave. Intravitreal 4-phosphono-butyric acid (APB) and cis-2,3-piperidine-dicarboxylic acid (PDA) were applied to isolate the photoreceptor response. The Hood and Birch version of the phototransduction model, Rmax[1 - e(-I x S x (t-t(eff)))2], was fitted to the a-wave data while allowing Rmax and S to vary. Three principle observations were made: (1) At flash intensities > or =0.77 log sc-td-s the leading edge of the normalized rod ERG a-wave tracks the isolated photoreceptor response across the first 20 ms or up to the point of b-wave intrusion. The rod ERG a-wave was essentially identical to the isolated receptor response for all intensities that produce peak responses within 14 ms after the flash. (2) The best fit of sensitivity (S) was not affected by APB and/or PDA, suggesting that the inner retina contributes very little to the dark-adapted a-wave. (3) APB always reduced the maximum dark-adapted a-wave amplitude (by 15-30%), and PDA always increased it (by 7-15%). Using the phototransduction model, both events can be interpreted as a scaling of the photoreceptor dark current. This suggests that activity of postreceptor cells somehow influences the rod dark current, possibly by feedback through horizontal cells (although currently not demonstrated for the rod system), or by altering the ionic concentrations near the photoreceptors, or by neuromodulator effects mediated by dopamine or

Cyclic GMP-gated CNG channels function in Sema3A-induced growth cone repulsion.

PubMed

Togashi, Kazunobu; von Schimmelmann, Melanie J; Nishiyama, Makoto; Lim, Chae-Seok; Yoshida, Norihiro; Yun, Bokyoung; Molday, Robert S; Goshima, Yoshio; Hong, Kyonsoo

2008-06-12

Cyclic nucleotide-gated channels (CNGCs) transduce external signals required for sensory processes, e.g., photoreception, olfaction, and taste. Nerve growth cone guidance by diffusible attractive and repulsive molecules is regulated by differential growth cone Ca2+ signaling. However, the Ca2+-conducting ion channels that transduce guidance molecule signals are largely unknown. We show that rod-type CNGC-like channels function in the repulsion of cultured Xenopus spinal neuron growth cones by Sema3A, which triggers the production of the cGMP that activates the Xenopus CNGA1 (xCNGA1) subunit-containing channels in interneurons. Downregulation of xCNGA1 or overexpression of a mutant xCNGA1 incapable of binding cGMP abolished CNG currents and converted growth cone repulsion to attraction in response to Sema3A. We also show that Ca2+ entry through xCNGCs is required to mediate the repulsive Sema3A signal. These studies extend our knowledge of the function of CNGCs by demonstrating their requirement for signal transduction in growth cone guidance.

Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects.

PubMed

Nikopoulos, Konstantinos; Farinelli, Pietro; Giangreco, Basilio; Tsika, Chrysanthi; Royer-Bertrand, Beryl; Mbefo, Martial K; Bedoni, Nicola; Kjellström, Ulrika; El Zaoui, Ikram; Di Gioia, Silvio Alessandro; Balzano, Sara; Cisarova, Katarina; Messina, Andrea; Decembrini, Sarah; Plainis, Sotiris; Blazaki, Styliani V; Khan, Muhammad Imran; Micheal, Shazia; Boldt, Karsten; Ueffing, Marius; Moulin, Alexandre P; Cremers, Frans P M; Roepman, Ronald; Arsenijevic, Yvan; Tsilimbaris, Miltiadis K; Andréasson, Sten; Rivolta, Carlo

2016-09-01

Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Photopigment quenching is Ca2+ dependent and controls response duration in salamander L-cone photoreceptors

PubMed Central

2010-01-01

The time scale of the photoresponse in photoreceptor cells is set by the slowest of the steps that quench the light-induced activity of the phototransduction cascade. In vertebrate photoreceptor cells, this rate-limiting reaction is thought to be either shutoff of catalytic activity in the photopigment or shutoff of the pigment's effector, the transducin-GTP–phosphodiesterase complex. In suction pipette recordings from isolated salamander L-cones, we found that preventing changes in internal [Ca2+] delayed the recovery of the light response and prolonged the dominant time constant for recovery. Evidence that the Ca2+-sensitive step involved the pigment itself was provided by the observation that removal of Cl− from the pigment's anion-binding site accelerated the dominant time constant for response recovery. Collectively, these observations indicate that in L-cones, unlike amphibian rods where the dominant time constant is insensitive to [Ca2+], pigment quenching rate limits recovery and provides an additional mechanism for modulating the cone response during light adaptation. PMID:20231373

Late-Onset Cone Photoreceptor Degeneration Induced by R172W Mutation in Rds and Partial Rescue by Gene Supplementation

PubMed Central

Conley, Shannon; Nour, May; Fliesler, Steven J.; Naash, Muna I.

2008-01-01

Purpose R172W is a common mutation in the human retinal degeneration slow (RDS) gene, associated with a late-onset dominant macular dystrophy. In this study, the authors characterized a mouse model that closely mimics the human phenotype and tested the feasibility of gene supplementation as a disease treatment strategy. Methods Transgenic mouse lines carrying the R172W mutation were generated. The retinal phenotype associated with this mutation in a low-expresser line (L-R172W) was examined, both structurally (histology with correlative immunohistochemistry) and functionally (electroretinography). By examining animals over time and with various rds genetic backgrounds, the authors evaluated the dominance of the defect. To assess the efficacy of gene transfer therapy as a treatment for this defect, a previously characterized transgenic line expressing the normal mouse peripherin/Rds (NMP) was crossed with a higher-expresser Rds line harboring the R172W mutation (H-R172W). Functional, structural, and biochemical analyses were used to assess rescue of the retinal disease phenotype. Results In the wild-type (WT) background, L-R172W mice exhibited late-onset (12-month) dominant cone degeneration without any apparent effect on rods. The degeneration was slightly accelerated (9 months) in the rds+/− background. L-R172W retinas did not form outer segments in the absence of endogenous Rds. With use of the H-R172W line on an rds+/− background for proof-of-principle genetic supplementation studies, the NMP transgene product rescued rod and cone functional defects and supported outer segment integrity up to 3 months of age, but the rescue effect did not persist in older (11-month) animals. Conclusions The R172W mutation leads to dominant cone degeneration in the mouse model, regardless of the expression level of the transgene. In contrast, effects of the mutation on rods are dose dependent, underscoring the usefulness of the L-R172W line as a faithful model of the human

Late-onset cone photoreceptor degeneration induced by R172W mutation in Rds and partial rescue by gene supplementation.

PubMed

Conley, Shannon; Nour, May; Fliesler, Steven J; Naash, Muna I

2007-12-01

R172W is a common mutation in the human retinal degeneration slow (RDS) gene, associated with a late-onset dominant macular dystrophy. In this study, the authors characterized a mouse model that closely mimics the human phenotype and tested the feasibility of gene supplementation as a disease treatment strategy. Transgenic mouse lines carrying the R172W mutation were generated. The retinal phenotype associated with this mutation in a low-expresser line (L-R172W) was examined, both structurally (histology with correlative immunohistochemistry) and functionally (electroretinography). By examining animals over time and with various rds genetic backgrounds, the authors evaluated the dominance of the defect. To assess the efficacy of gene transfer therapy as a treatment for this defect, a previously characterized transgenic line expressing the normal mouse peripherin/Rds (NMP) was crossed with a higher-expresser Rds line harboring the R172W mutation (H-R172W). Functional, structural, and biochemical analyses were used to assess rescue of the retinal disease phenotype. In the wild-type (WT) background, L-R172W mice exhibited late-onset (12-month) dominant cone degeneration without any apparent effect on rods. The degeneration was slightly accelerated (9 months) in the rds(+/-) background. L-R172W retinas did not form outer segments in the absence of endogenous Rds. With use of the H-R172W line on an rds(+/-) background for proof-of-principle genetic supplementation studies, the NMP transgene product rescued rod and cone functional defects and supported outer segment integrity up to 3 months of age, but the rescue effect did not persist in older (11-month) animals. The R172W mutation leads to dominant cone degeneration in the mouse model, regardless of the expression level of the transgene. In contrast, effects of the mutation on rods are dose dependent, underscoring the usefulness of the L-R172W line as a faithful model of the human phenotype. This model may prove

Reconstruction-of-difference (RoD) imaging for cone-beam CT neuro-angiography

NASA Astrophysics Data System (ADS)

Wu, P.; Stayman, J. W.; Mow, M.; Zbijewski, W.; Sisniega, A.; Aygun, N.; Stevens, R.; Foos, D.; Wang, X.; Siewerdsen, J. H.

2018-06-01

Timely evaluation of neurovasculature via CT angiography (CTA) is critical to the detection of pathology such as ischemic stroke. Cone-beam CTA (CBCT-A) systems provide potential advantages in the timely use at the point-of-care, although challenges of a relatively slow gantry rotation speed introduce tradeoffs among image quality, data consistency and data sparsity. This work describes and evaluates a new reconstruction-of-difference (RoD) approach that is robust to such challenges. A fast digital simulation framework was developed to test the performance of the RoD over standard reference reconstruction methods such as filtered back-projection (FBP) and penalized likelihood (PL) over a broad range of imaging conditions, grouped into three scenarios to test the trade-off between data consistency, data sparsity and peak contrast. Two experiments were also conducted using a CBCT prototype and an anthropomorphic neurovascular phantom to test the simulation findings in real data. Performance was evaluated primarily in terms of normalized root mean square error (NRMSE) in comparison to truth, with reconstruction parameters chosen to optimize performance in each case to ensure fair comparison. The RoD approach reduced NRMSE in reconstructed images by up to 50%–53% compared to FBP and up to 29%–31% compared to PL for each scenario. Scan protocols well suited to the RoD approach were identified that balance tradeoffs among data consistency, sparsity and peak contrast—for example, a CBCT-A scan with 128 projections acquired in 8.5 s over a 180°  +  fan angle half-scan for a time attenuation curve with ~8.5 s time-to-peak and 600 HU peak contrast. With imaging conditions such as the simulation scenarios of fixed data sparsity (i.e. varying levels of data consistency and peak contrast), the experiments confirmed the reduction of NRMSE by 34% and 17% compared to FBP and PL, respectively. The RoD approach demonstrated superior performance in 3D angiography

Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene.

PubMed Central

Pinard, J M; Motte, J; Chiron, C; Brian, R; Andermann, E; Dulac, O

1994-01-01

Neuronal migration disorders can now be recognised by MRI. This paper reports two families in which the mothers had subcortical laminar heterotopia and four of their children had either similar heterotopia (two girls) or severe pachygyria or lissencephaly (two boys). Laminar heterotopia was more evident on MRI T2 weighted images. The patients had mild to severe epilepsy and mental retardation depending on the extent of cortical abnormalities. In these families, subcortical laminar heterotopia, pachygyria, and lissencephaly seem to share the same X linked or autosomal dominant gene. No chromosomal abnormalities, especially of chromosome 17, could be identified. For appropriate genetic counselling of the family of a child with lissencephaly or subcortical laminar heterotopia, MRI should be performed in parents or siblings with mental retardation or epilepsy. Images PMID:8057113

Expression of the vesicular glutamate transporter vGluT2 in a subset of cones of the mouse retina.

PubMed

Wässle, Heinz; Regus-Leidig, Hanna; Haverkamp, Silke

2006-06-01

Cone photoreceptors have a continuous release of glutamate that is modulated by light. Vesicular glutamate transporters (vGluT) play an essential role for sustaining this release by loading synaptic vesicles in the cone synapse, the so-called cone pedicle. In the present study mouse retinas were immunostained for vGluT1 and vGluT2. vGluT1 was localized to all cone pedicles and rod spherules, whereas vGluT2 was found in only 10% of the cone pedicles. The vGluT2-expressing cones were characterized in more detail. They are distributed in a regular array, suggesting they are a distinct type. Their proportion does not differ between dorsal (L-cone-dominated) and ventral (S-cone-dominated) retina, and they are not the genuine blue cones of the mouse retina. During development, vGluT1 and vGluT2 expression in cones starts at around P0 and right from the beginning vGluT2 is only expressed in a subset of cones. Bipolar cells contact the vGluT2-expressing cones and other cones nonselectively. The possible functional role of vGluT2 expression in a small fraction of cones is discussed.

Cat colour vision: one cone process or several?

PubMed Central

Daw, N. W.; Pearlman, A. L.

1969-01-01

1. Peripheral mechanisms that might contribute to colour vision in the cat have been investigated by recording from single units in the lateral geniculate and optic tract. Evidence is presented that the input to these cells comes from a single class of cones with a single spectral sensitivity. 2. In cats with pupils dilated a background level of 10-30 cd/m2 was sufficient to saturate the rod system for all units. When the rods were saturated, the spectral sensitivity of all units peaked at 556 nm; this was true both for centre and periphery of the receptive field. The spectral sensitivity curve was slightly narrower than the Dartnall nomogram. It could not be shifted by chromatic adaptation with red, green, blue or yellow backgrounds. 3. In the mesopic range (0·1-10 cd/m2), the threshold could be predicted in terms of two mechanisms, a cone mechanism with spectral sensitivity peaking at 556 nm, and a rod mechanism with spectral sensitivity at 500 nm. The mechanisms were separated and their increment threshold curves measured by testing with one colour against a background of another colour. All units had input from both rods and cones. The changeover from rods to cones occurred at the same level of adaptation in both centre and periphery of the receptive field. Threshold for the cones was between 0·04 and 0·25 cd/m2 with the pupil dilated, for a spot covering the centre of the receptive field. 4. None of the results was found to vary between lateral geniculate and optic tract, with layer in the lateral geniculate, or with distance from area centralis in the visual field. 5. The lack of evidence for more than one cone type suggests that colour discrimination in the cat may be a phenomenon of mesopic vision, based on differences in spectral sensitivity of the rods and a single class of cones. PMID:5767891

Scalable diode array pumped Nd rod laser

NASA Technical Reports Server (NTRS)

Zenzie, H. H.; Knights, M. G.; Mosto, J. R.; Chicklis, E. P.; Perkins, P. E.

1991-01-01

Experiments were carried out on a five-array pump head which utilizes gold-coated reflective cones to couple the pump energy to Nd:YAG and Nd:YLF rod lasers, demonstrating high efficiency and uniform energy deposition. Because the cones function as optical diodes to light outside their acceptance angle (typically 10-15 deg), much of the diode energy not absorbed on the first pass can be returned to the rod.

Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone-rod dystrophy phenotype in an Italian family.

PubMed

Simonelli, Francesca; Testa, Francesco; Zernant, Jana; Nesti, Anna; Rossi, Settimio; Rinaldi, Ernesto; Allikmets, Rando

2004-01-01

Genetic variation in the ABCA4 (ABCR) gene has been associated with several distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), retinitis pigmentosa (RP) and age-related macular degeneration. The current model of genotype/phenotype association suggests that patients harboring deleterious mutations in both ABCR alleles would develop RP-like retinal pathology. Here we describe ABCA4-associated phenotypes, including a proband with a homozygous nonsense mutation in a family from Southern Italy. The proband had been originally diagnosed with STGD. Ophthalmologic examination included kinetic perimetry, electrophysiological studies and fluorescein angiography. DNA of the affected individual and family members was analyzed for variants in all 50 exons of the ABCA4 gene by screening on the ABCR400 microarray. A homozygous nonsense mutation 2971G>T (G991X) was detected in a patient initially diagnosed with STGD based on funduscopic evidence, including bull's eye depigmentation of the fovea and flecks at the posterior pole extending to the mid-peripheral retina. Since this novel nucleotide substitution results in a truncated, nonfunctional, ABCA4 protein, the patient was examined in-depth for the severity of the disease phenotype. Indeed, subsequent electrophysiological studies determined severely reduced cone amplitude as compared to the rod amplitude, suggesting the diagnosis of CRD. ABCR400 microarray is an efficient tool for determining causal genetic variation, including new mutations. A homozygous protein-truncating mutation in ABCA4 can cause a phenotype ranging from STGD to CRD as diagnosed at an early stage of the disease. Only a combination of comprehensive genotype/phenotype correlation studies will determine the proper diagnosis and prognosis of ABCA4-associated pathology. Copyright 2004 S. Karger AG, Basel

Severe manifestations in carrier females in X linked retinitis pigmentosa.

PubMed Central

Souied, E; Segues, B; Ghazi, I; Rozet, J M; Chatelin, S; Gerber, S; Perrault, I; Michel-Awad, A; Briard, M L; Plessis, G; Dufier, J L; Munnich, A; Kaplan, J

1997-01-01

Retinitis pigmentosa (RP) is a group of progressive hereditary disorders of the retina in which various modes of inheritance have been described. Here, we report on X linked RP in nine families with constant and severe expression in carrier females. In our series, however, the phenotype was milder and delayed in carrier females compared to hemizygous males. This form of X linked RP could be regarded therefore as partially dominant. The disease gene maps to chromosome Xp2.1 in the genetic interval encompassing the RP3 locus (Zmax=13.71 at the DXS1100 locus). Single strand conformation polymorphism and direct sequence analysis of the retinitis pigmentosa GTPase regulator (RPGR) gene, which accounts for RP3, failed to detect any mutation in our families. Future advances in the identification of X linked RP genes will hopefully help to elucidate the molecular basis of this X linked dominant RP. Images PMID:9350809

Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs.

PubMed

Jalili, I K

2010-11-01

To report a new phenotype with additional data on the oculo-dental syndrome of cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) caused by mutations on CNNM4, a metal transporter, with linkage at achromatopsia locus 2q11 (Jalili syndrome). Three siblings aged 5, 6, and 10 years from a six-generation Arab family in Gaza City underwent full systemic, ophthalmic, and dental examinations, investigations and detailed genealogy. Subjects presented at early childhood with visual impairment and abnormal dentition together with photophobia and fine nystagmus increasing under photopic conditions, in the presence of normal fundi. Electrophysiologically, photopic flicker responses were impaired; scotopic responses were extinguished at the age of 10 years. Anterior open bite accompanied AI in all siblings. The syndrome formed 83% of CRD cases in the Gaza Strip, which has a prevalence of 1 : 10,000. On the basis of clinical features and electrophysiology, two phenotypes exist: an infancy onset form with progressive macular lesion and an early childhood onset form with normal fundi. More prevalent than previously thought, Jalili syndrome presents a model of the effect of different mutations of the same genetic defect, observations of the same phenotype at different stages of the natural history of the disease, and the influence of epigenetic and tissue-specific factors as causes of phenotypic variability. The paper calls for action to tackle consanguinity in endogamous communities, addresses the possible role of high fluoride levels in groundwater as a trigger for genetic mutations, and the use of red-tinted filter in cone disorders.

Genotypic analysis of X-linked retinoschisis in Western Australia.

PubMed

Lamey, Tina; Laurin, Sarina; Chelva, Enid; De Roach, John

2010-01-01

X-linked Retinoschisis is a leading cause of juvenile macular degeneration. Four Western Australian families affected by X-Linked Retinoschisis were analysed using DNA and clinical information from the Australian Inherited Retinal Disease (IRD) Register and DNA Bank. By direct sequencing of the RS1 gene, three genetic variants were identified; 52+1G > T, 289T > G and 416delA. 289T > G has not been previously reported and is likely to cause a substitution of a membrane binding residue (W92G) in the functional discoidin domain. All clinically diagnosed individuals showed typical electronegative ERGs. The 52+1G > T obligate carrier also recorded a bilaterally abnormal rod ERG and mildly abnormal photopic responses. mfERG trace arrays showed reduced response densities in the paramacular region extending futher temporally for each eye.

Cone beam x-ray luminescence computed tomography: a feasibility study.

PubMed

Chen, Dongmei; Zhu, Shouping; Yi, Huangjian; Zhang, Xianghan; Chen, Duofang; Liang, Jimin; Tian, Jie

2013-03-01

The appearance of x-ray luminescence computed tomography (XLCT) opens new possibilities to perform molecular imaging by x ray. In the previous XLCT system, the sample was irradiated by a sequence of narrow x-ray beams and the x-ray luminescence was measured by a highly sensitive charge coupled device (CCD) camera. This resulted in a relatively long sampling time and relatively low utilization of the x-ray beam. In this paper, a novel cone beam x-ray luminescence computed tomography strategy is proposed, which can fully utilize the x-ray dose and shorten the scanning time. The imaging model and reconstruction method are described. The validity of the imaging strategy has been studied in this paper. In the cone beam XLCT system, the cone beam x ray was adopted to illuminate the sample and a highly sensitive CCD camera was utilized to acquire luminescent photons emitted from the sample. Photons scattering in biological tissues makes it an ill-posed problem to reconstruct the 3D distribution of the x-ray luminescent sample in the cone beam XLCT. In order to overcome this issue, the authors used the diffusion approximation model to describe the photon propagation in tissues, and employed the sparse regularization method for reconstruction. An incomplete variables truncated conjugate gradient method and permissible region strategy were used for reconstruction. Meanwhile, traditional x-ray CT imaging could also be performed in this system. The x-ray attenuation effect has been considered in their imaging model, which is helpful in improving the reconstruction accuracy. First, simulation experiments with cylinder phantoms were carried out to illustrate the validity of the proposed compensated method. The experimental results showed that the location error of the compensated algorithm was smaller than that of the uncompensated method. The permissible region strategy was applied and reduced the reconstruction error to less than 2 mm. The robustness and stability were then

Rapid kinetics of endocytosis at rod photoreceptor synapses depends upon endocytic load and calcium.

PubMed

Cork, Karlene M; Thoreson, Wallace B

2014-05-01

Release from rods is triggered by the opening of L-type Ca2+ channels that lie beneath synaptic ribbons. After exocytosis, vesicles are retrieved by compensatory endocytosis. Previous work showed that endocytosis is dynamin-dependent in rods but dynamin-independent in cones. We hypothesized that fast endocytosis in rods may also differ from cones in its dependence upon the amount of Ca2+ influx and/or endocytic load. We measured exocytosis and endocytosis from membrane capacitance (C m) changes evoked by depolarizing steps in voltage clamped rods from tiger salamander retinal slices. Similar to cones, the time constant for endocytosis in rods was quite fast, averaging <200 ms. We manipulated Ca2+ influx and the amount of vesicle release by altering the duration and voltage of depolarizing steps. Unlike cones, endocytosis kinetics in rods slowed after increasing Ca2+ channel activation with longer step durations or more strongly depolarized voltage steps. Endocytosis kinetics also slowed as Ca2+ buffering was decreased by replacing BAPTA (10 or 1 mM) with the slower Ca2+ buffer EGTA (5 or 0.5 mM) in the pipette solution. These data provide further evidence that endocytosis mechanisms differ in rods and cones and suggest that endocytosis in rods is regulated by both endocytic load and local Ca2+ levels.

Rapid kinetics of endocytosis at rod photoreceptor synapses depends upon endocytic load and calcium

PubMed Central

CORK, KARLENE M.; THORESON, WALLACE B.

2015-01-01

Release from rods is triggered by the opening of L-type Ca2+ channels that lie beneath synaptic ribbons. After exocytosis, vesicles are retrieved by compensatory endocytosis. Previous work showed that endocytosis is dynamin-dependent in rods but dynamin-independent in cones. We hypothesized that fast endocytosis in rods may also differ from cones in its dependence upon the amount of Ca2+ influx and/or endocytic load. We measured exocytosis and endocytosis from membrane capacitance (Cm) changes evoked by depolarizing steps in voltage clamped rods from tiger salamander retinal slices. Similar to cones, the time constant for endocytosis in rods was quite fast, averaging <200 ms. We manipulated Ca2+ influx and the amount of vesicle release by altering the duration and voltage of depolarizing steps. Unlike cones, endocytosis kinetics in rods slowed after increasing Ca2+ channel activation with longer step durations or more strongly depolarized voltage steps. Endocytosis kinetics also slowed as Ca2+ buffering was decreased by replacing BAPTA (10 or 1 mM) with the slower Ca2+ buffer EGTA (5 or 0.5 mM) in the pipette solution. These data provide further evidence that endocytosis mechanisms differ in rods and cones and suggest that endocytosis in rods is regulated by both endocytic load and local Ca2+ levels. PMID:24735554

Language dominance, handedness and sex: recessive X-linkage theory and test.

PubMed

Jones, Gregory V; Martin, Maryanne

2010-06-01

The possibility is investigated that cerebral dominance for language and handedness share a common X-linkage and that the relation between the two is therefore a function of sex. In particular, an X-linked recessive account is shown to predict an overall configuration of language dominance, handedness and sex within which there is a sex effect in the pattern of language dominance among right-handed but not left-handed people. The recent accurate determination of cerebral dominance among relatively large samples of the general population by means of functional transcranial Doppler ultrasonography makes it possible to test this new theory rigorously, and its parameter-free pattern of predictions is found to be supported. Copyright (c) 2009 Elsevier Srl. All rights reserved.

Mouse cones require an arrestin for normal inactivation of phototransduction.

PubMed

Nikonov, Sergei S; Brown, Bruce M; Davis, Jason A; Zuniga, Freddi I; Bragin, Alvina; Pugh, Edward N; Craft, Cheryl M

2008-08-14

Arrestins are proteins that arrest the activity of G protein-coupled receptors (GPCRs). While it is well established that normal inactivation of photoexcited rhodopsin, the GPCR of rod phototransduction, requires arrestin (Arr1), it has been controversial whether the same requirement holds for cone opsin inactivation. Mouse cone photoreceptors express two distinct visual arrestins: Arr1 and Arr4. By means of recordings from cones of mice with one or both arrestins knocked out, this investigation establishes that a visual arrestin is required for normal cone inactivation. Arrestin-independent inactivation is 70-fold more rapid in cones than in rods, however. Dual arrestin expression in cones could be a holdover from ancient genome duplication events that led to multiple isoforms of arrestin, allowing evolutionary specialization of one form while the other maintains the basic function.

Brain perfusion imaging using a Reconstruction-of-Difference (RoD) approach for cone-beam computed tomography

NASA Astrophysics Data System (ADS)

Mow, M.; Zbijewski, W.; Sisniega, A.; Xu, J.; Dang, H.; Stayman, J. W.; Wang, X.; Foos, D. H.; Koliatsos, V.; Aygun, N.; Siewerdsen, J. H.

2017-03-01

Purpose: To improve the timely detection and treatment of intracranial hemorrhage or ischemic stroke, recent efforts include the development of cone-beam CT (CBCT) systems for perfusion imaging and new approaches to estimate perfusion parameters despite slow rotation speeds compared to multi-detector CT (MDCT) systems. This work describes development of a brain perfusion CBCT method using a reconstruction of difference (RoD) approach to enable perfusion imaging on a newly developed CBCT head scanner prototype. Methods: A new reconstruction approach using RoD with a penalized-likelihood framework was developed to image the temporal dynamics of vascular enhancement. A digital perfusion simulation was developed to give a realistic representation of brain anatomy, artifacts, noise, scanner characteristics, and hemo-dynamic properties. This simulation includes a digital brain phantom, time-attenuation curves and noise parameters, a novel forward projection method for improved computational efficiency, and perfusion parameter calculation. Results: Our results show the feasibility of estimating perfusion parameters from a set of images reconstructed from slow scans, sparse data sets, and arc length scans as short as 60 degrees. The RoD framework significantly reduces noise and time-varying artifacts from inconsistent projections. Proper regularization and the use of overlapping reconstructed arcs can potentially further decrease bias and increase temporal resolution, respectively. Conclusions: A digital brain perfusion simulation with RoD imaging approach has been developed and supports the feasibility of using a CBCT head scanner for perfusion imaging. Future work will include testing with data acquired using a 3D-printed perfusion phantom currently and translation to preclinical and clinical studies.

Effects of ionizing radiation on the light sensing elements of the retina. [Structural and physiological effects of carbon, helium, and neon ions on rods and cones of salamanders and mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Malachowski, M.J.

1978-07-01

This investigation was undertaken to quantitate possible morphological and physiological effects of particles of high linear energy transfer on the retina, in comparison with x-ray effects. The particles used were accelerated atomic nuclei of helium, carbon, and neon at kinetic energies of several hundred MeV/nucleon. For morphological studies, scanning and transmission electron microscopy and light microscopy were used. Physiological studies consisted of autoradiographic data of the rate of incorporation of labeled protein in the structures (opsin) of the outer segment of visual cells. Structural changes were found in the nuclei, as well as the inner and outer segments of visualmore » cells, rods and cones. At a low dose of 10 rad, x rays and helium had no statistically significant morphological effects, but carbon and neon beams did cause significant degeneration of individual cells, pointing to the existence of a linear dose--effect relationship. At high doses of several hundred rads, a Pathologic Index determined the relative biological effectiveness of neon against alpha particles to have a value of greater than 6. The severity of effects per particle increased with atomic number. Labeling studies demonstrated a decreased rate of incorporation of labeled proteins in the structural organization of the outer segments of visual rods. The rate of self-renewal of visual rod discs was punctuated by irradiation and the structures themselves were depleted of amino acids. A model of rod discs (metabolic and catabolic) was postulated for correlated early and late effects to high and low doses.« less

A previously unreported, dominantly inherited syndrome of shortness of stature, ear malformations, and hip dislocation: the coxoauricular syndrome--autosomal or X-linked male-lethal.

PubMed

Duca, D; Pană, I; Ciovirnache, M; Simionesu, L; Ispas, I; Maxililian, C

1981-01-01

We reported an apparently previously undescribed syndrome, designated the coxoauricular syndrome, in a mother and her 3 daughters, all of whom shared in variable manner shortness of stature, minor vertebral and pelvic changes, dislocated hip(s), and microtia with corresponding hearing loss. The oldest daughter had coincidental Ullrich-Turner syndrome with 46, Xdel(X)(q 13) chromosome constitution. Inheritance of the trait in this family is dominant, either autosomal or X-linked, with hemizygote lethality.

RodZ links MreB to cell wall synthesis to mediate MreB rotation and robust morphogenesis

PubMed Central

Morgenstein, Randy M.; Bratton, Benjamin P.; Nguyen, Jeffrey P.; Ouzounov, Nikolay; Shaevitz, Joshua W.; Gitai, Zemer

2015-01-01

The rod shape of most bacteria requires the actin homolog, MreB. Whereas MreB was initially thought to statically define rod shape, recent studies found that MreB dynamically rotates around the cell circumference dependent on cell wall synthesis. However, the mechanism by which cytoplasmic MreB is linked to extracytoplasmic cell wall synthesis and the function of this linkage for morphogenesis has remained unclear. Here we demonstrate that the transmembrane protein RodZ mediates MreB rotation by directly or indirectly coupling MreB to cell wall synthesis enzymes. Furthermore, we map the RodZ domains that link MreB to cell wall synthesis and identify mreB mutants that suppress the shape defect of ΔrodZ without restoring rotation, uncoupling rotation from rod-like growth. Surprisingly, MreB rotation is dispensable for rod-like shape determination under standard laboratory conditions but is required for the robustness of rod shape and growth under conditions of cell wall stress. PMID:26396257

RodZ links MreB to cell wall synthesis to mediate MreB rotation and robust morphogenesis.

PubMed

Morgenstein, Randy M; Bratton, Benjamin P; Nguyen, Jeffrey P; Ouzounov, Nikolay; Shaevitz, Joshua W; Gitai, Zemer

2015-10-06

The rod shape of most bacteria requires the actin homolog, MreB. Whereas MreB was initially thought to statically define rod shape, recent studies found that MreB dynamically rotates around the cell circumference dependent on cell wall synthesis. However, the mechanism by which cytoplasmic MreB is linked to extracytoplasmic cell wall synthesis and the function of this linkage for morphogenesis has remained unclear. Here we demonstrate that the transmembrane protein RodZ mediates MreB rotation by directly or indirectly coupling MreB to cell wall synthesis enzymes. Furthermore, we map the RodZ domains that link MreB to cell wall synthesis and identify mreB mutants that suppress the shape defect of ΔrodZ without restoring rotation, uncoupling rotation from rod-like growth. Surprisingly, MreB rotation is dispensable for rod-like shape determination under standard laboratory conditions but is required for the robustness of rod shape and growth under conditions of cell wall stress.

NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP).

PubMed

Schorderet, Daniel F; Escher, Pascal

2009-11-01

NR2E3, also called photoreceptor-specific nuclear receptor (PNR), is a transcription factor of the nuclear hormone receptor superfamily whose expression is uniquely restricted to photoreceptors. There, its physiological activity is essential for proper rod and cone photoreceptor development and maintenance. Thirty-two different mutations in NR2E3 have been identified in either homozygous or compound heterozygous state in the recessively inherited enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD). The clinical phenotype common to all these patients is night blindness, rudimental or absent rod function, and hyperfunction of the "blue" S-cones. A single p.G56R mutation is inherited in a dominant manner and causes retinitis pigmentosa (RP). We have established a new locus-specific database for NR2E3 (www.LOVD.nl/eye), containing all reported mutations, polymorphisms, and unclassified sequence variants, including novel ones. A high proportion of mutations are located in the evolutionarily-conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) of NR2E3. Based on homology modeling of these NR2E3 domains, we propose a structural localization of mutated residues. The high variability of clinical phenotypes observed in patients affected by NR2E3-linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA-binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes.

Paternal inheritance of classic X-linked bilateral periventricular nodular heterotopia.

PubMed

Kasper, Burkhard S; Kurzbuch, Katrin; Chang, Bernard S; Pauli, Elisabeth; Hamer, Hajo M; Winkler, Jürgen; Hehr, Ute

2013-06-01

Periventricular nodular heterotopia (PNH) is a developmental disorder of the central nervous system, characterized by heterotopic nodules of gray matter resulting from disturbed neuronal migration. The most common form of bilateral PNH is X-linked dominant inherited, caused by mutations in the Filamin A gene (FLNA) and associated with a wide variety of other clinical findings including congenital heart disease. The typical patient with FLNA-associated PNH is female and presents with difficult to treat seizures. In contrast, hemizygous FLNA loss of function mutations in males are reported to be perinatally lethal. In X-linked dominant traits like FLNA-associated PNH the causal mutation is commonly inherited from the mother. Here, we present an exceptional family with paternal transmission of classic bilateral FLNA-associated PNH from a mildly affected father with somatic and germline mosaicism for a c.5686G>A FLNA splice mutation to both daughters with strikingly variable clinical manifestation and PNH extent in cerebral MR imaging. Our observations emphasize the importance to consider in genetic counseling and risk assessment the rare genetic constellation of paternal transmission for families with X-linked dominant inherited FLNA-associated PNH. Copyright © 2013 Wiley Periodicals, Inc.

Correlation between spectral-domain OCT findings and visual acuity in X-linked retinoschisis.

PubMed

Yang, Hyun Seung; Lee, Jung Bok; Yoon, Young Hee; Lee, Joo Yong

2014-05-08

To investigate the tomographic characteristics of the outer retina and choroid and their relationship with visual acuity in X-linked juvenile retinoschisis (XLRS) patients using spectral-domain optical coherence tomography (SD-OCT). In this retrospective, observational, case-control study, we analyzed 20 eyes of 10 patients with XLRS using SD-OCT. The clinical and tomographic features of the outer retina, including the external limiting membrane (ELM), inner segment/outer segment (IS/OS) junction, cone cell outer segment tips (COST) line, photoreceptor outer segment (PROS) length, and choroid, were evaluated. As controls, 40 age-, sex-, and refraction-matched healthy eyes (1:2 matched) were randomly selected and imaged in parallel. The most prevalent area of abnormality in the outer retina layer of our patients was the outer plexiform layer (OPL; 60% of all affected eyes) and COST line (75% of all affected eyes). On average, the subfoveal choroid and PROS lengths were 35 μm thicker and 19 μm thinner, respectively, in XLRS patients (P = 0.084 and P < 0.001, respectively). A dominant IS/OS junction, COST line defects, and PROS length were related to patient best-corrected visual acuity (BCVA; P = 0.029, P = 0.001, and P < 0.001, respectively) by univariate analysis. Cone cell outer segment tips line defect and PROS length were the only factors related to BCVA in multivariate analysis (P = 0.028 and 0.003, respectively). Outer plexiform layer and photoreceptor microstructure defects are frequent in XLRS patients. Cone cell outer segment tips line defects and shortened PROS lengths as well as other photoreceptor microstructure defects may be closely related to poor vision in XLRS.

RPE65 gene therapy slows cone loss in Rpe65-deficient dogs.

PubMed

Mowat, F M; Breuwer, A R; Bartoe, J T; Annear, M J; Zhang, Z; Smith, A J; Bainbridge, J W B; Petersen-Jones, S M; Ali, R R

2013-05-01

Recent clinical trials of retinal pigment epithelium gene (RPE65) supplementation therapy in Leber congenital amaurosis type 2 patients have demonstrated improvements in rod and cone function, but it may be some years before the effects of therapy on photoreceptor survival become apparent. The Rpe65-deficient dog is a very useful pre-clinical model in which to test efficacy of therapies, because the dog has a retina with a high degree of similarity to that of humans. In this study, we evaluated the effect of RPE65 gene therapy on photoreceptor survival in order to predict the potential benefit and limitations of therapy in patients. We examined the retinas of Rpe65-deficient dogs after RPE65 gene therapy to evaluate the preservation of rods and cone photoreceptor subtypes. We found that gene therapy preserves both rods and cones. While the moderate loss of rods in the Rpe65-deficient dog retina is slowed by gene therapy, S-cones are lost extensively and gene therapy can prevent that loss, although only within the treated area. Although LM-cones are not lost extensively, cone opsin mislocalization indicates that they are stressed, and this can be partially reversed by gene therapy. Our results suggest that gene therapy may be able to slow cone degeneration in patients if intervention is sufficiently early and also that it is probably important to treat the macula in order to preserve central function.

Cone Beam X-Ray Luminescence Tomography Imaging Based on KA-FEM Method for Small Animals.

PubMed

Chen, Dongmei; Meng, Fanzhen; Zhao, Fengjun; Xu, Cao

2016-01-01

Cone beam X-ray luminescence tomography can realize fast X-ray luminescence tomography imaging with relatively low scanning time compared with narrow beam X-ray luminescence tomography. However, cone beam X-ray luminescence tomography suffers from an ill-posed reconstruction problem. First, the feasibility of experiments with different penetration and multispectra in small animal has been tested using nanophosphor material. Then, the hybrid reconstruction algorithm with KA-FEM method has been applied in cone beam X-ray luminescence tomography for small animals to overcome the ill-posed reconstruction problem, whose advantage and property have been demonstrated in fluorescence tomography imaging. The in vivo mouse experiment proved the feasibility of the proposed method.

Adult-onset cerebello-brainstem dominant form of X-linked adrenoleukodystrophy presenting as multiple system atrophy: Case report and literature review

PubMed Central

Ogaki, Kotaro; Koga, Shunsuke; Aoki, Naoya; Lin, Wenlang; Suzuki, Kinuko; Ross, Owen A.; Dickson, Dennis W.

2015-01-01

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello-brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy confirmed cases exceedingly rare. We report a 69-year-old white man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X-ALD or Addison’s disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities, and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss, and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of multiple system atrophy. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS-positive, CD68-positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft-like trilamellar cytoplasmic inclusions in macrophages typical of X-ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello-brainstem dominant form of X-ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult-onset cerebello-brainstem dominant form of X-ALD. Although rare, X-ALD should be

High sensitivity rod photoreceptor input to the blue-yellow color opponent pathway in macaque retina

PubMed Central

Field, Greg D.; Greschner, Martin; Gauthier, Jeffrey L.; Rangel, Carolina; Shlens, Jonathon; Sher, Alexander; Marshak, David W.; Litke, Alan M.; Chichilnisky, E.J.

2009-01-01

Small bistratified cells (SBCs) in the primate retina carry a major blue-yellow opponent signal to the brain. Here we show that SBCs also carry signals from rod photoreceptors, with the same sign as S cone input. SBCs exhibited robust responses under low scotopic conditions (<0.01 P*/rod/s). Physiological and anatomical experiments indicated that this rod input arose from the AII amacrine cell mediated rod pathway. Rod and cone signals were both present in SBCs at mesopic light levels. We discuss three implications of these findings. First, more retinal circuits than previously thought may multiplex rod and cone signals, efficiently exploiting the limited number of optic nerve fibers. Second, signals from AII amacrine cells may diverge to most or all of the <20 RGC types in the peripheral primate retina. Third, rod input to SBCs may be the substrate for behavioral biases toward perception of blue at mesopic light levels. PMID:19668201

Generation of three-dimensional retinal organoids expressing rhodopsin and S- and M-cone opsins from mouse stem cells.

PubMed

Ueda, Kaori; Onishi, Akishi; Ito, Shin-Ichiro; Nakamura, Makoto; Takahashi, Masayo

2018-01-22

Three-dimensional retinal organoids can be differentiated from embryonic stem cells/induced pluripotent stem cells (ES/iPS cells) under defined medium conditions. We modified the serum-free floating culture of embryoid body-like aggregates with quick reaggregation (SFEBq) culture procedure to obtain retinal organoids expressing more rod photoreceptors and S- and M-cone opsins. Retinal organoids differentiated from mouse Nrl-eGFP iPS cells were cultured in various mediums during photoreceptor development. To promote rod photoreceptor development, organoids were maintained in media containing 9-cis retinoic acids (9cRA). To obtain retinal organoids with M-opsin expression, we cultured in medium with 1% fetal bovine serum (FBS) supplemented with T3, BMP4, and DAPT. Section immunohistochemistry was performed to visualize the expression of photoreceptor markers. In three-dimensional (3D) retinas exposed to 9cRA, rhodopsin was expressed earlier and S-cone opsins were suppressed. We could maintain 3D retinas up to DD 35 in culture media with 1% FBS. The 3D retinas expressed rhodopsin, S- and M-opsins, but most cone photoreceptors expressed either S- or M-opsins. By modifying culture conditions in the SFEBq protocol, we obtained rod-dominated 3D retinas and S- and M-opsin expressing 3D retinas. Copyright © 2017 Elsevier Inc. All rights reserved.

X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria

PubMed Central

Brancaleoni, V.; Balwani, M.; Granata, F.; Graziadei, G.; Missineo, P.; Fiorentino, V.; Fustinoni, S.; Cappellini, M.D.; Naik, H.; Desnick, R.J.; Di Pierro, E.

2015-01-01

X-linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain-of-function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X-linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X-chromsomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc-finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X-chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild-type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin-containing peripheral blood fluorocytes. When the wild-type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP. PMID:25615817

The absolute threshold of cone vision

PubMed Central

Koeing, Darran; Hofer, Heidi

2013-01-01

We report measurements of the absolute threshold of cone vision, which has been previously underestimated due to sub-optimal conditions or overly strict subjective response criteria. We avoided these limitations by using optimized stimuli and experimental conditions while having subjects respond within a rating scale framework. Small (1′ fwhm), brief (34 msec), monochromatic (550 nm) stimuli were foveally presented at multiple intensities in dark-adapted retina for 5 subjects. For comparison, 4 subjects underwent similar testing with rod-optimized stimuli. Cone absolute threshold, that is, the minimum light energy for which subjects were just able to detect a visual stimulus with any response criterion, was 203 ± 38 photons at the cornea, ∼0.47 log units lower than previously reported. Two-alternative forced-choice measurements in a subset of subjects yielded consistent results. Cone thresholds were less responsive to criterion changes than rod thresholds, suggesting a limit to the stimulus information recoverable from the cone mosaic in addition to the limit imposed by Poisson noise. Results were consistent with expectations for detection in the face of stimulus uncertainty. We discuss implications of these findings for modeling the first stages of human cone vision and interpreting psychophysical data acquired with adaptive optics at the spatial scale of the receptor mosaic. PMID:21270115

Purinergic modulation of frog electroretinographic responses: The role of the ionotropic receptor P2X7.

PubMed

Kupenova, Petia; Popova, Elka; Vitanova, Liliya

2017-01-01

The contribution of the purinergic receptors P2X7 (P2X7Rs) to the electroretinographic (ERG) responses was studied by testing the effects of the selective P2X7R antagonist A438079 and the selective P2X7R agonist Bz-ATP on the electroretinograms obtained in perfused frog (Rana ridibunda) eyecup preparations under a variety of stimulation conditions. The P2X7R blockade by 200 µM A438079 diminished the amplitude of the photoreceptor components: the a-wave and the pharmacologically isolated mass receptor potential. In the pure rod-driven and pure cone-driven responses, the amplitude of the postreceptoral ON (b-wave) and OFF (d-wave) components was also diminished. The OFF responses were affected to a greater extent compared to the ON responses. In the mixed rod- and cone-driven responses, obtained in the mesopic intensity range, the b-wave amplitude was increased, while the d-wave amplitude was decreased. The amplitude of the oscillatory potentials was diminished. The relative amplitude changes produced by the P2X7R blockade were greater in the dark-adapted compared to the light-adapted eyes. The application of 100 µM Bz-ATP produced small effects opposite to those of the antagonist, while a prolonged (>20 min) treatment with 1 mM Bz-ATP resulted in a significant amplitude reduction or even abolishment of b- and d-waves. Our results show that endogenous ATP through its P2X7Rs exerts significant, mostly potentiating effects on the ERG photoreceptor and postreceptoral responses. There is a clear ON/OFF asymmetry of the effects on the ERG postreceptoral responses favoring OFF responses: they are always strongly potentiated, while the ON responses are either less potentiated (in the rod-driven and most of the cone-driven responses) or even inhibited (in the mixed rod- and cone-driven responses). The overstimulation of P2X7Rs can produce acute pathological changes, that is, a decrease or abolishment of the ERG responses.

Mineralized rods and cones suggest colour vision in a 300 Myr-old fossil fish.

PubMed

Tanaka, Gengo; Parker, Andrew R; Hasegawa, Yoshikazu; Siveter, David J; Yamamoto, Ryoichi; Miyashita, Kiyoshi; Takahashi, Yuichi; Ito, Shosuke; Wakamatsu, Kazumasa; Mukuda, Takao; Matsuura, Marie; Tomikawa, Ko; Furutani, Masumi; Suzuki, Kayo; Maeda, Haruyoshi

2014-12-23

Vision, which consists of an optical system, receptors and image-processing capacity, has existed for at least 520 Myr. Except for the optical system, as in the calcified lenses of trilobite and ostracod arthropods, other parts of the visual system are not usually preserved in the fossil record, because the soft tissue of the eye and the brain decay rapidly after death, such as within 64 days and 11 days, respectively. The Upper Carboniferous Hamilton Formation (300 Myr) in Kansas, USA, yields exceptionally well-preserved animal fossils in an estuarine depositional setting. Here we show that the original colour, shape and putative presence of eumelanin have been preserved in the acanthodii fish Acanthodes bridgei. We also report on the tissues of its eye, which provides the first record of mineralized rods and cones in a fossil and indicates that this 300 Myr-old fish likely possessed colour vision.

Cone Beam X-ray Luminescence Computed Tomography Based on Bayesian Method.

PubMed

Zhang, Guanglei; Liu, Fei; Liu, Jie; Luo, Jianwen; Xie, Yaoqin; Bai, Jing; Xing, Lei

2017-01-01

X-ray luminescence computed tomography (XLCT), which aims to achieve molecular and functional imaging by X-rays, has recently been proposed as a new imaging modality. Combining the principles of X-ray excitation of luminescence-based probes and optical signal detection, XLCT naturally fuses functional and anatomical images and provides complementary information for a wide range of applications in biomedical research. In order to improve the data acquisition efficiency of previously developed narrow-beam XLCT, a cone beam XLCT (CB-XLCT) mode is adopted here to take advantage of the useful geometric features of cone beam excitation. Practically, a major hurdle in using cone beam X-ray for XLCT is that the inverse problem here is seriously ill-conditioned, hindering us to achieve good image quality. In this paper, we propose a novel Bayesian method to tackle the bottleneck in CB-XLCT reconstruction. The method utilizes a local regularization strategy based on Gaussian Markov random field to mitigate the ill-conditioness of CB-XLCT. An alternating optimization scheme is then used to automatically calculate all the unknown hyperparameters while an iterative coordinate descent algorithm is adopted to reconstruct the image with a voxel-based closed-form solution. Results of numerical simulations and mouse experiments show that the self-adaptive Bayesian method significantly improves the CB-XLCT image quality as compared with conventional methods.

Cone Beam X-ray Luminescence Computed Tomography Based on Bayesian Method

PubMed Central

Liu, Fei; Luo, Jianwen; Xie, Yaoqin; Bai, Jing

2017-01-01

X-ray luminescence computed tomography (XLCT), which aims to achieve molecular and functional imaging by X-rays, has recently been proposed as a new imaging modality. Combining the principles of X-ray excitation of luminescence-based probes and optical signal detection, XLCT naturally fuses functional and anatomical images and provides complementary information for a wide range of applications in biomedical research. In order to improve the data acquisition efficiency of previously developed narrow-beam XLCT, a cone beam XLCT (CB-XLCT) mode is adopted here to take advantage of the useful geometric features of cone beam excitation. Practically, a major hurdle in using cone beam X-ray for XLCT is that the inverse problem here is seriously ill-conditioned, hindering us to achieve good image quality. In this paper, we propose a novel Bayesian method to tackle the bottleneck in CB-XLCT reconstruction. The method utilizes a local regularization strategy based on Gaussian Markov random field to mitigate the ill-conditioness of CB-XLCT. An alternating optimization scheme is then used to automatically calculate all the unknown hyperparameters while an iterative coordinate descent algorithm is adopted to reconstruct the image with a voxel-based closed-form solution. Results of numerical simulations and mouse experiments show that the self-adaptive Bayesian method significantly improves the CB-XLCT image quality as compared with conventional methods. PMID:27576245

The limit of photoreceptor sensitivity: molecular mechanisms of dark noise in retinal cones.

PubMed

Holcman, David; Korenbrot, Juan I

2005-06-01

Detection threshold in cone photoreceptors requires the simultaneous absorption of several photons because single photon photocurrent is small in amplitude and does not exceed intrinsic fluctuations in the outer segment dark current (dark noise). To understand the mechanisms that limit light sensitivity, we characterized the molecular origin of dark noise in intact, isolated bass single cones. Dark noise is caused by continuous fluctuations in the cytoplasmic concentrations of both cGMP and Ca(2+) that arise from the activity in darkness of both guanylate cyclase (GC), the enzyme that synthesizes cGMP, and phosphodiesterase (PDE), the enzyme that hydrolyzes it. In cones loaded with high concentration Ca(2+) buffering agents, we demonstrate that variation in cGMP levels arise from fluctuations in the mean PDE enzymatic activity. The rates of PDE activation and inactivation determine the quantitative characteristics of the dark noise power density spectrum. We developed a mathematical model based on the dynamics of PDE activity that accurately predicts this power spectrum. Analysis of the experimental data with the theoretical model allows us to determine the rates of PDE activation and deactivation in the intact photoreceptor. In fish cones, the mean lifetime of active PDE at room temperature is approximately 55 ms. In nonmammalian rods, in contrast, active PDE lifetime is approximately 555 ms. This remarkable difference helps explain why cones are noisier than rods and why cone photocurrents are smaller in peak amplitude and faster in time course than those in rods. Both these features make cones less light sensitive than rods.

Functional significance of the taper of vertebrate cone photoreceptors

PubMed Central

Hárosi, Ferenc I.

2012-01-01

Vertebrate photoreceptors are commonly distinguished based on the shape of their outer segments: those of cones taper, whereas the ones from rods do not. The functional advantages of cone taper, a common occurrence in vertebrate retinas, remain elusive. In this study, we investigate this topic using theoretical analyses aimed at revealing structure–function relationships in photoreceptors. Geometrical optics combined with spectrophotometric and morphological data are used to support the analyses and to test predictions. Three functions are considered for correlations between taper and functionality. The first function proposes that outer segment taper serves to compensate for self-screening of the visual pigment contained within. The second function links outer segment taper to compensation for a signal-to-noise ratio decline along the longitudinal dimension. Both functions are supported by the data: real cones taper more than required for these compensatory roles. The third function relates outer segment taper to the optical properties of the inner compartment whereby the primary determinant is the inner segment’s ability to concentrate light via its ellipsoid. In support of this idea, the rod/cone ratios of primarily diurnal animals are predicted based on a principle of equal light flux gathering between photoreceptors. In addition, ellipsoid concentration factor, a measure of ellipsoid ability to concentrate light onto the outer segment, correlates positively with outer segment taper expressed as a ratio of characteristic lengths, where critical taper is the yardstick. Depending on a light-funneling property and the presence of focusing organelles such as oil droplets, cone outer segments can be reduced in size to various degrees. We conclude that outer segment taper is but one component of a miniaturization process that reduces metabolic costs while improving signal detection. Compromise solutions in the various retinas and retinal regions occur between

Transcription map of Xq27: candidates for several X-linked diseases.

PubMed

Zucchi, I; Jones, J; Affer, M; Montagna, C; Redolfi, E; Susani, L; Vezzoni, P; Parvari, R; Schlessinger, D; Whyte, M P; Mumm, S

1999-04-15

Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found. Copyright 1999 Academic Press.

Functional role of hCngb3 in regulation of human cone cng channel: effect of rod monochromacy-associated mutations in hCNGB3 on channel function.

PubMed

Okada, Akira; Ueyama, Hisao; Toyoda, Futoshi; Oda, Sanae; Ding, Wei-Guang; Tanabe, Shoko; Yamade, Shinichi; Matsuura, Hiroshi; Ohkubo, Iwao; Kani, Kazutaka

2004-07-01

The human cone photoreceptor cyclic nucleotide-gated (CNG) channel comprises alpha- and beta-subunits, which are respectively encoded by hCNGA3 and hCNGB3. The purpose was to examine the functional role of hCNGB3 in modulation of human cone CNG channels and to characterize functional consequences of rod monochromacy-associated mutations in hCNGB3 (S435F and D633G). Macroscopic patch currents were recorded from human embryonic kidney (HEK) 293 cells expressing homomeric (hCNGA3 and hCNGB3) and heteromeric (hCNGA3/hCNGB3, hCNGA3/hCNGB3-S435F, and hCNGA3/hCNGB3-D633G) channels using inside-out patch-clamp technique. Both hCNGA3 homomeric and hCNGA3/hCNGB3 heteromeric channels were activated by cGMP, with half-maximally activating concentration (K(1/2)) of 11.1 +/- 1.0 and 26.2 +/- 1.9 micro M, respectively. The hCNGA3 channels appeared to be more sensitive to inhibition by extracellular Ca(2+) compared with hCNGA3/hCNGB3 channels, when assessed by the degree of outward rectification. Coexpression of either of rod monochromacy-associated mutants of hCNGB3 with hCNGA3 significantly reduced K(1/2) value for cGMP but little affected the sensitivity to extracellular Ca(2+), compared with wild-type heteromeric channels. The selectivity of hCNGA3, hCNGA3/hCNGB3, hCNGA3/hCNGB3-S435F, and hCNGA3/hCNGB3-D633G channels for monovalent cations were largely similar. Immunoprecipitation experiments showed association of hCNGA3 subunit with both of wild-type and mutant hCNGB3 subunits. The hCNGB3 plays an important modulatory role in the function of human cone CNG channels with respect to cGMP and extracellular Ca(2+) sensitivities. The rod monochromacy-associated S435F and D633G mutations in hCNGB3 evokes a significant increase in the apparent affinity for cGMP, which should alter cone function and thereby contribute at least partly to pathogenesis of the disease.

Recombinant adeno-associated virus targets passenger gene expression to cones in primate retina

NASA Astrophysics Data System (ADS)

Mancuso, Katherine; Hendrickson, Anita E.; Connor, Thomas B., Jr.; Mauck, Matthew C.; Kinsella, James J.; Hauswirth, William W.; Neitz, Jay; Neitz, Maureen

2007-05-01

Recombinant adeno-associated virus (rAAV) is a promising vector for gene therapy of photoreceptor-based diseases. Previous studies have demonstrated that rAAV serotypes 2 and 5 can transduce both rod and cone photoreceptors in rodents and dogs, and it can target rods, but not cones in primates. Here we report that using a human cone-specific enhancer and promoter to regulate expression of a green fluorescent protein (GFP) reporter gene in an rAAV-5 vector successfully targeted expression of the reporter gene to primate cones, and the time course of GFP expression was able to be monitored in a living animal using the RetCam II digital imaging system.

Noninvasive imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope

PubMed Central

Dubra, Alfredo; Sulai, Yusufu; Norris, Jennifer L.; Cooper, Robert F.; Dubis, Adam M.; Williams, David R.; Carroll, Joseph

2011-01-01

The rod photoreceptors are implicated in a number of devastating retinal diseases. However, routine imaging of these cells has remained elusive, even with the advent of adaptive optics imaging. Here, we present the first in vivo images of the contiguous rod photoreceptor mosaic in nine healthy human subjects. The images were collected with three different confocal adaptive optics scanning ophthalmoscopes at two different institutions, using 680 and 775 nm superluminescent diodes for illumination. Estimates of photoreceptor density and rod:cone ratios in the 5°–15° retinal eccentricity range are consistent with histological findings, confirming our ability to resolve the rod mosaic by averaging multiple registered images, without the need for additional image processing. In one subject, we were able to identify the emergence of the first rods at approximately 190 μm from the foveal center, in agreement with previous histological studies. The rod and cone photoreceptor mosaics appear in focus at different retinal depths, with the rod mosaic best focus (i.e., brightest and sharpest) being at least 10 μm shallower than the cones at retinal eccentricities larger than 8°. This study represents an important step in bringing high-resolution imaging to bear on the study of rod disorders. PMID:21750765

Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia.

PubMed

Baum, Michel; Syal, Ashu; Quigley, Raymond; Seikaly, Mouin

2006-08-01

X-linked hypophosphatemia is an X-linked dominant disorder resulting from a mutation in the PHEX gene. PHEX stands for phosphate-regulating gene with endopeptidase activity, which is located on the X chromosome. Patients with X-linked hypophosphatemia have hypophosphatemia due to renal phosphate wasting and low or inappropriately normal levels of 1,25-dihydroxyvitamin D. The renal phosphate wasting is not intrinsic to the kidney but likely due to an increase in serum levels of fibroblast growth factor-23 (FGF-23), and perhaps other phosphate-wasting peptides previously known as phosphatonins. Patients with X-linked hypophosphatemia have short stature, rickets, bone pain and dental abscesses. Current therapy is oral phosphate and vitamin D which effectively treats the rickets and bone pain but does not adequately improve short stature. In this review, we describe recent observations using Hyp mice; mice with the same mutation as patients with X-linked hypophosphatemia. We have recently found that Hyp mice have abnormal renal prostaglandin production, which may be an important factor in the pathogenesis of this disorder. Administration of FGF-23 in vivo results in phosphaturia and an increase in prostaglandin excretion, and FGF-23 increases proximal tubule prostaglandin production in vitro. In Hyp mice, indomethacin improves the phosphate transport defect in vitro and in vivo. Whether indomethacin has the same effect in patients with X-linked hypophosphatemia is unknown.

Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ionasescu, V.; Ionasescu, R.; Searby, C.

1996-06-14

We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these familiesmore » showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size. 25 refs., 1 fig., 1 tab.« less

Functional Optical Coherence Tomography Enables In Vivo Physiological Assessment of Retinal Rod and Cone Photoreceptors

PubMed Central

Zhang, Qiuxiang; Lu, Rongwen; Wang, Benquan; Messinger, Jeffrey D.; Curcio, Christine A.; Yao, Xincheng

2015-01-01

Transient intrinsic optical signal (IOS) changes have been observed in retinal photoreceptors, suggesting a unique biomarker for eye disease detection. However, clinical deployment of IOS imaging is challenging due to unclear IOS sources and limited signal-to-noise ratios (SNRs). Here, by developing high spatiotemporal resolution optical coherence tomography (OCT) and applying an adaptive algorithm for IOS processing, we were able to record robust IOSs from single-pass measurements. Transient IOSs, which might reflect an early stage of light phototransduction, are consistently observed in the photoreceptor outer segment almost immediately (<4 ms) after retinal stimulation. Comparative studies of dark- and light-adapted retinas have demonstrated the feasibility of functional OCT mapping of rod and cone photoreceptors, promising a new method for early disease detection and improved treatment of diseases such as age-related macular degeneration (AMD) and other eye diseases that can cause photoreceptor damage. PMID:25901915

Functional Optical Coherence Tomography Enables In Vivo Physiological Assessment of Retinal Rod and Cone Photoreceptors

NASA Astrophysics Data System (ADS)

Zhang, Qiuxiang; Lu, Rongwen; Wang, Benquan; Messinger, Jeffrey D.; Curcio, Christine A.; Yao, Xincheng

2015-04-01

Transient intrinsic optical signal (IOS) changes have been observed in retinal photoreceptors, suggesting a unique biomarker for eye disease detection. However, clinical deployment of IOS imaging is challenging due to unclear IOS sources and limited signal-to-noise ratios (SNRs). Here, by developing high spatiotemporal resolution optical coherence tomography (OCT) and applying an adaptive algorithm for IOS processing, we were able to record robust IOSs from single-pass measurements. Transient IOSs, which might reflect an early stage of light phototransduction, are consistently observed in the photoreceptor outer segment almost immediately (<4 ms) after retinal stimulation. Comparative studies of dark- and light-adapted retinas have demonstrated the feasibility of functional OCT mapping of rod and cone photoreceptors, promising a new method for early disease detection and improved treatment of diseases such as age-related macular degeneration (AMD) and other eye diseases that can cause photoreceptor damage.

Recapitulation of Human Retinal Development from Human Pluripotent Stem Cells Generates Transplantable Populations of Cone Photoreceptors.

PubMed

Gonzalez-Cordero, Anai; Kruczek, Kamil; Naeem, Arifa; Fernando, Milan; Kloc, Magdalena; Ribeiro, Joana; Goh, Debbie; Duran, Yanai; Blackford, Samuel J I; Abelleira-Hervas, Laura; Sampson, Robert D; Shum, Ian O; Branch, Matthew J; Gardner, Peter J; Sowden, Jane C; Bainbridge, James W B; Smith, Alexander J; West, Emma L; Pearson, Rachael A; Ali, Robin R

2017-09-12

Transplantation of rod photoreceptors, derived either from neonatal retinae or pluripotent stem cells (PSCs), can restore rod-mediated visual function in murine models of inherited blindness. However, humans depend more upon cone photoreceptors that are required for daylight, color, and high-acuity vision. Indeed, macular retinopathies involving loss of cones are leading causes of blindness. An essential step for developing stem cell-based therapies for maculopathies is the ability to generate transplantable human cones from renewable sources. Here, we report a modified 2D/3D protocol for generating hPSC-derived neural retinal vesicles with well-formed ONL-like structures containing cones and rods bearing inner segments and connecting cilia, nascent outer segments, and presynaptic structures. This differentiation system recapitulates human photoreceptor development, allowing the isolation and transplantation of a pure population of stage-matched cones. Purified human long/medium cones survive and become incorporated within the adult mouse retina, supporting the potential of photoreceptor transplantation for treating retinal degeneration. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

3D algebraic iterative reconstruction for cone-beam x-ray differential phase-contrast computed tomography.

PubMed

Fu, Jian; Hu, Xinhua; Velroyen, Astrid; Bech, Martin; Jiang, Ming; Pfeiffer, Franz

2015-01-01

Due to the potential of compact imaging systems with magnified spatial resolution and contrast, cone-beam x-ray differential phase-contrast computed tomography (DPC-CT) has attracted significant interest. The current proposed FDK reconstruction algorithm with the Hilbert imaginary filter will induce severe cone-beam artifacts when the cone-beam angle becomes large. In this paper, we propose an algebraic iterative reconstruction (AIR) method for cone-beam DPC-CT and report its experiment results. This approach considers the reconstruction process as the optimization of a discrete representation of the object function to satisfy a system of equations that describes the cone-beam DPC-CT imaging modality. Unlike the conventional iterative algorithms for absorption-based CT, it involves the derivative operation to the forward projections of the reconstructed intermediate image to take into account the differential nature of the DPC projections. This method is based on the algebraic reconstruction technique, reconstructs the image ray by ray, and is expected to provide better derivative estimates in iterations. This work comprises a numerical study of the algorithm and its experimental verification using a dataset measured with a three-grating interferometer and a mini-focus x-ray tube source. It is shown that the proposed method can reduce the cone-beam artifacts and performs better than FDK under large cone-beam angles. This algorithm is of interest for future cone-beam DPC-CT applications.

Pyoderma Gangrenosum–Like Ulcer in a Patient With X-Linked Agammaglobulinemia

PubMed Central

Murray, Patrick R.; Jain, Ashish; Uzel, Gulbu; Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B.; Ecker, David J.; Sampath, Rangarajan; Lee, Chyi-Chia Richard; Turner, Maria L.

2011-01-01

Background Pyoderma gangrenosum–like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient’s culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. Observation An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when sub-cultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. Conclusions This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum–like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum–like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy. PMID:20479300

Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Qing-lin; Xu, Jia; Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233

2012-07-13

Highlights: Black-Right-Pointing-Pointer In our study, all of the patients were of Han Chinese ethnicity, which were rarely reported. Black-Right-Pointing-Pointer We identified three novel PHEX gene mutations in four unrelated families with XLH. Black-Right-Pointing-Pointer We found that the relationship between the phenotype and genotype of the PHEX gene was not invariant. Black-Right-Pointing-Pointer We found that two PHEX gene sites, p.534 and p.731, were conserved. -- Abstract: Background: X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is a dominant disorder that is characterized by renal phosphate wasting with hypophosphatemia, abnormal bone mineralization, short stature, and rachitic manifestations. The related genemore » with inactivating mutations associated with XLH has been identified as PHEX, which is a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In this study, a variety of PHEX mutations were identified in four Chinese families with XLH. Methods: We investigated four unrelated Chinese families who exhibited typical features of XLH by using PCR to analyze mutations that were then sequenced. The laboratory and radiological investigations were conducted simultaneously. Results: Three novel mutations were found in these four families: one frameshift mutation, c.2033dupT in exon 20, resulting in p.T679H; one nonsense mutation, c.1294A > T in exon 11, resulting in p.K432X; and one missense mutation, c.2192T > C in exon 22, resulting in p.F731S. Conclusions: We found that the PHEX gene mutations were responsible for XLH in these Chinese families. Our findings are useful for understanding the genetic basis of Chinese patients with XLH.« less

Malformations among 289,365 Births Attributed to Mutations with Autosomal Dominant and Recessive and X-Linked Inheritance.

PubMed

Toufaily, M Hassan; Westgate, Marie-Noel; Nasri, Hanah; Holmes, Lewis B

2018-01-01

The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders. The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well. One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents. It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Rod-driven OFF pathway responses in the distal retina: dark-adapted flicker electroretinogram in mouse.

PubMed

Lei, Bo

2012-01-01

The rodent retina does not exhibit a positive OFF-response in the electroretinogram (ERG), which makes it difficult to evaluate its OFF-pathway functions in vivo. We studied the rod-driven OFF pathway responses by using a dark-adapted 10-Hz flicker ERG procedure in mouse. Conventional ERGs and 10-Hz dark-adapted flicker ERGs were obtained in wild-type mice (C57BL/6), in mice with pure rod (cpfl1) or pure cone (rho(-/-)) function, and in nob1 mice which have a selective ON-pathway defect. To isolate the response from ON or OFF pathway, glutamate analogs 2-amino-4-phosphobutyric acid (APB, an ON pathway blocker) and cis-2, 3-piperidine-dicarboxylic acid (PDA, an OFF pathway blocker), were injected intravitreally. The amplitude-intensity profile of the dark-adapted 10-Hz flicker ERG in the wild-type mice exhibits two peaks at middle and high light intensities. The two peaks represent rod- and cone-driven responses respectively. In APB-treated C57BL/6 mice and in nob1 mice, the dark-adapted ERG b-waves were absent. However, both rod- and cone-driven OFF pathway responses were evident with flicker ERG recording. At middle light intensities that activate only rod system, the flicker ERG responses in saline-injected nob1 mice were similar to those in APB-injected cpfl1 mice and wild-type mice. These responses are sensitive to PDA. The amplitudes of these rod-driven OFF pathway responses were approximately 20% of the total rod-driven flicker ERG responses. We demonstrate that the rod-OFF bipolar cell pathway is functional in the outer retina. The dark-adapted flicker ERG is practical for the evaluation of rod- and cone-driven responses, and the residual OFF pathway signals in subjects with ON pathway defects.

Why do seals have cones? Behavioural evidence for colour-blindness in harbour seals.

PubMed

Scholtyssek, Christine; Kelber, Almut; Dehnhardt, Guido

2015-03-01

All seals and cetaceans have lost at least one of two ancestral cone classes and should therefore be colour-blind. Nevertheless, earlier studies showed that these marine mammals can discriminate colours and a colour vision mechanism has been proposed which contrasts signals from cones and rods. However, these earlier studies underestimated the brightness discrimination abilities of these animals, so that they could have discriminated colours using brightness only. Using a psychophysical discrimination experiment, we showed that a harbour seal can solve a colour discrimination task by means of brightness discrimination alone. Performing a series of experiments in which two harbour seals had to discriminate the brightness of colours, we also found strong evidence for purely scotopic (rod-based) vision at light levels that lead to mesopic (rod-cone-based) vision in other mammals. This finding speaks against rod-cone-based colour vision in harbour seals. To test for colour-blindness, we used a cognitive approach involving a harbour seal trained to use a concept of same and different. We tested this seal with pairs of isoluminant stimuli that were either same or different in colour. If the seal had perceived colour, it would have responded to colour differences between stimuli. However, the seal responded with "same", providing strong evidence for colour-blindness.

Visual Cone Arrestin 4 Contributes to Visual Function and Cone Health.

PubMed

Deming, Janise D; Pak, Joseph S; Brown, Bruce M; Kim, Moon K; Aung, Moe H; Eom, Yun Sung; Shin, Jung-A; Lee, Eun-Jin; Pardue, Machelle T; Craft, Cheryl Mae

2015-08-01

Visual arrestins (ARR) play a critical role in shutoff of rod and cone phototransduction. When electrophysiological responses are measured for a single mouse cone photoreceptor, ARR1 expression can substitute for ARR4 in cone pigment desensitization; however, each arrestin may also contribute its own, unique role to modulate other cellular functions. A combination of ERG, optokinetic tracking, immunohistochemistry, and immunoblot analysis was used to investigate the retinal phenotypes of Arr4 null mice (Arr4-/-) compared with age-matched control, wild-type mice. When 2-month-old Arr4-/- mice were compared with wild-type mice, they had diminished visual acuity and contrast sensitivity, yet enhanced ERG flicker response and higher photopic ERG b-wave amplitudes. In contrast, in older Arr4-/- mice, all ERG amplitudes were significantly reduced in magnitude compared with age-matched controls. Furthermore, in older Arr4-/- mice, the total cone numbers decreased and cone opsin protein immunoreactive expression levels were significantly reduced, while overall photoreceptor outer nuclear layer thickness was unchanged. Our study demonstrates that Arr4-/- mice display distinct phenotypic differences when compared to controls, suggesting that ARR4 modulates essential functions in high acuity vision and downstream cellular signaling pathways that are not fulfilled or substituted by the coexpression of ARR1, despite its high expression levels in all mouse cones. Without normal ARR4 expression levels, cones slowly degenerate with increasing age, making this a new model to study age-related cone dystrophy.

Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice

PubMed Central

Venkatesh, Aditya; Ma, Shan; Le, Yun Z.; Hall, Michael N.; Rüegg, Markus A.; Punzo, Claudio

2015-01-01

Retinitis pigmentosa (RP) is an inherited photoreceptor degenerative disorder that results in blindness. The disease is often caused by mutations in genes that are specific to rod photoreceptors; however, blindness results from the secondary loss of cones by a still unknown mechanism. Here, we demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) is required to slow the progression of cone death during disease and that constitutive activation of mTORC1 in cones is sufficient to maintain cone function and promote long-term cone survival. Activation of mTORC1 in cones enhanced glucose uptake, retention, and utilization, leading to increased levels of the key metabolite NADPH. Moreover, cone death was delayed in the absence of the NADPH-sensitive cell death protease caspase 2, supporting the contribution of reduced NADPH in promoting cone death. Constitutive activation of mTORC1 preserved cones in 2 mouse models of RP, suggesting that the secondary loss of cones is caused mainly by metabolic deficits and is independent of a specific rod-associated mutation. Together, the results of this study address a longstanding question in the field and suggest that activating mTORC1 in cones has therapeutic potential to prolong vision in RP. PMID:25798619

Cat colour vision: evidence for more than one cone process

PubMed Central

Daw, N. W.; Pearlman, A. L.

1970-01-01

1. The ability of cats to distinguish colours was investigated at mesopic and photopic levels to test the hypothesis that cats discriminate wavelength by using rods in conjunction with a single type of cone. 2. Cats were trained to distinguish red from cyan, and orange from cyan at the mesopic level. They retained the ability to make this discrimination when the coloured stimuli were placed against a background bright enough to saturate the rods. 3. One cat was also tested after being exposed to a bright white light of 9000 cd/m2 for a period of 5 min, and found able to distinguish red from cyan. 4. These results suggest that cats have more than one type of cone. Subsequent recordings from single units in the lateral geniculate nucleus showed that there are rare opponent colour units in layer B with input from a green-absorbing cone and a blue-absorbing cone. ImagesPlate 1 PMID:5500987

Cone Structure in Retinal Degeneration Associated with Mutations in the peripherin/RDS Gene

PubMed Central

Talcott, Katherine E.; Ratnam, Kavitha; Sundquist, Sanna M.; Lucero, Anya S.; Day, Shelley; Zhang, Yuhua; Roorda, Austin

2011-01-01

Purpose. To study cone photoreceptor structure and function associated with mutations in the second intradiscal loop region of peripherin/RDS. Methods. High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy and spectral domain optical coherence tomography in four patients with peripherin/RDS mutations and 27 age-similar healthy subjects. Measures of retinal structure and fundus autofluorescence (AF) were correlated with visual function, including best-corrected visual acuity (BCVA), kinetic and static perimetry, fundus-guided microperimetry, full-field electroretinography (ERG), and multifocal ERG. The coding regions of the peripherin/RDS gene were sequenced in each patient. Results. Heterozygous mutations in peripherin/RDS were predicted to affect protein structure in the second intradiscal domain in each patient (Arg172Trp, Gly208Asp, Pro210Arg and Cys213Tyr). BCVA was at least 20/32 in the study eye of each patient. Diffuse cone-greater-than-rod dysfunction was present in patient 1, while rod-greater-than-cone dysfunction was present in patient 4; macular outer retinal dysfunction was present in all patients. Macular AF was heterogeneous, and the photoreceptor-retinal pigment epithelial (RPE) junction layer showed increased reflectivity at the fovea in all patients except patient 1, who showed cone-rod dystrophy. Cone packing was irregular, and cone spacing was significantly increased (z-scores >2) at most locations throughout the central 4° in each patient. Conclusions. peripherin/RDS mutations produced diffuse AF abnormalities, disruption of the photoreceptor/RPE junction, and increased cone spacing, consistent with cone loss in the macula. The abnormalities observed suggest that the integrity of the second intradiscal domain of peripherin/RDS is critical for normal macular cone structure. PMID:21071739

cis Retinol oxidation regulates photoreceptor access to the retina visual cycle and cone pigment regeneration

PubMed Central

Sato, Shinya

2016-01-01

Key points This study explores the nature of the cis retinol that Müller cells in the retina provide to cones for the regeneration of their visual pigment.We report that the retina visual cycle provides cones exclusively with 11‐cis chromophore in both salamander and mouse and show that this selectivity is dependent on the 11‐cis‐specific cellular retinaldehyde binding protein (CRALBP) present in Müller cells.Even though salamander blue cones and green rods share the same visual pigment, only blue cones but not green rods are able to dark‐adapt in the retina following a bleach and to use exogenous 9‐cis retinol for pigment regeneration, suggesting that access to the retina visual cycle is cone‐specific and pigment‐independent.Our results show that the retina produces 11‐cis retinol that can be oxidized and used for pigment regeneration and dark adaptation selectively in cones and not in rods. Abstract Chromophore supply by the retinal Müller cells (retina visual cycle) supports the efficient pigment regeneration required for cone photoreceptor function in bright light. Surprisingly, a large fraction of the chromophore produced by dihydroceramide desaturase‐1, the putative all‐trans retinol isomerase in Müller cells, appears to be 9‐cis retinol. In contrast, the canonical retinal pigment epithelium (RPE) visual cycle produces exclusively 11‐cis retinal. Here, we used the different absorption spectra of 9‐cis and 11‐cis pigments to identify the isoform of the chromophore produced by the visual cycle of the intact retina. We found that the spectral sensitivity of salamander and mouse cones dark‐adapted in the isolated retina (with only the retina visual cycle) was similar to that of cones dark‐adapted in the intact eye (with both the RPE and retina visual cycles) and consistent with pure 11‐cis pigment composition. However, in mice lacking the cellular retinaldehyde binding protein (CRALBP), cone spectral sensitivity contained a

Dynamic near-infrared imaging reveals transient phototropic change in retinal rod photoreceptors.

PubMed

Lu, Rongwen; Levy, Alexander M; Zhang, Qiuxiang; Pittler, Steven J; Yao, Xincheng

2013-10-01

Stiles-Crawford effect (SCE) is exclusively observed in cone photoreceptors, but why the SCE is absent in rod photoreceptors is still a mystery. In this study, we employed dynamic near infrared light imaging to monitor photoreceptor kinetics in freshly isolated frog and mouse retinas stimulated by oblique visible light flashes. It was observed that retinal rods could rapidly (onset: ∼10 ms for frog and 5 ms for mouse; time-to-peak: ∼200 ms for frog and 30 ms for mouse) shift toward the direction of the visible light, which might quickly compensate for the loss of luminous efficiency due to oblique illumination. In contrast, such directional movement was negligible in retinal cones. Moreover, transient rod phototropism could contribute to characteristic intrinsic optical signal (IOS). We anticipate that further study of the transient rod phototropism may not only provide insight into better understanding of the nature of vision but also promise an IOS biomarker for functional mapping of rod physiology at high resolution.

Early-onset, slow progression of cone photoreceptor dysfunction and degeneration in CNG channel subunit CNGB3 deficiency.

PubMed

Xu, Jianhua; Morris, Lynsie; Fliesler, Steven J; Sherry, David M; Ding, Xi-Qin

2011-06-01

To investigate the progression of cone dysfunction and degeneration in CNG channel subunit CNGB3 deficiency. Retinal structure and function in CNGB3(-/-) and wild-type (WT) mice were evaluated by electroretinography (ERG), lectin cytochemistry, and correlative Western blot analysis of cone-specific proteins. Cone and rod terminal integrity was assessed by electron microscopy and synaptic protein immunohistochemical distribution. Cone ERG amplitudes (photopic b-wave) in CNGB3(-/-) mice were reduced to approximately 50% of WT levels by postnatal day 15, decreasing further to approximately 30% of WT levels by 1 month and to approximately 20% by 12 months of age. Rod ERG responses (scotopic a-wave) were not affected in CNGB3(-/-) mice. Average CNGB3(-/-) cone densities were approximately 80% of WT levels at 1 month and declined slowly thereafter to only approximately 50% of WT levels by 12 months. Expression levels of M-opsin, cone transducin α-subunit, and cone arrestin in CNGB3(-/-) mice were reduced by 50% to 60% by 1 month and declined to 35% to 45% of WT levels by 9 months. In addition, cone opsin mislocalized to the outer nuclear layer and the outer plexiform layer in the CNGB3(-/-) retina. Cone and rod synaptic marker expression and terminal ultrastructure were normal in the CNGB3(-/-) retina. These findings are consistent with an early-onset, slow progression of cone functional defects and cone loss in CNGB3(-/-) mice, with the cone signaling deficits arising from disrupted phototransduction and cone loss rather than from synaptic defects.

The giant mottled eel, Anguilla marmorata, uses blue-shifted rod photoreceptors during upstream migration.

PubMed

Wang, Feng-Yu; Fu, Wen-Chun; Wang, I-Li; Yan, Hong Young; Wang, Tzi-Yuan

2014-01-01

Catadromous fishes migrate between ocean and freshwater during particular phases of their life cycle. The dramatic environmental changes shape their physiological features, e.g. visual sensitivity, olfactory ability, and salinity tolerance. Anguilla marmorata, a catadromous eel, migrates upstream on dark nights, following the lunar cycle. Such behavior may be correlated with ontogenetic changes in sensory systems. Therefore, this study was designed to identify changes in spectral sensitivity and opsin gene expression of A. marmorata during upstream migration. Microspectrophotometry analysis revealed that the tropical eel possesses a duplex retina with rod and cone photoreceptors. The λmax of rod cells are 493, 489, and 489 nm in glass, yellow, and wild eels, while those of cone cells are 508, and 517 nm in yellow, and wild eels, respectively. Unlike European and American eels, Asian eels exhibited a blue-shifted pattern of rod photoreceptors during upstream migration. Quantitative gene expression analyses of four cloned opsin genes (Rh1f, Rh1d, Rh2, and SWS2) revealed that Rh1f expression is dominant at all three stages, while Rh1d is expressed only in older yellow eel. Furthermore, sequence comparison and protein modeling studies implied that a blue shift in Rh1d opsin may be induced by two known (N83, S292) and four putative (S124, V189, V286, I290) tuning sites adjacent to the retinal binding sites. Finally, expression of blue-shifted Rh1d opsin resulted in a spectral shift in rod photoreceptors. Our observations indicate that the giant mottled eel is color-blind, and its blue-shifted scotopic vision may influence its upstream migration behavior and habitat choice.

Visual Cone Arrestin 4 Contributes to Visual Function and Cone Health

PubMed Central

Deming, Janise D.; Pak, Joseph S.; Brown, Bruce M.; Kim, Moon K.; Aung, Moe H.; Eom, Yun Sung; Shin, Jung-a; Lee, Eun-Jin; Pardue, Machelle T.; Craft, Cheryl Mae

2015-01-01

Purpose Visual arrestins (ARR) play a critical role in shutoff of rod and cone phototransduction. When electrophysiological responses are measured for a single mouse cone photoreceptor, ARR1 expression can substitute for ARR4 in cone pigment desensitization; however, each arrestin may also contribute its own, unique role to modulate other cellular functions. Methods A combination of ERG, optokinetic tracking, immunohistochemistry, and immunoblot analysis was used to investigate the retinal phenotypes of Arr4 null mice (Arr4−/−) compared with age-matched control, wild-type mice. Results When 2-month-old Arr4−/− mice were compared with wild-type mice, they had diminished visual acuity and contrast sensitivity, yet enhanced ERG flicker response and higher photopic ERG b-wave amplitudes. In contrast, in older Arr4−/− mice, all ERG amplitudes were significantly reduced in magnitude compared with age-matched controls. Furthermore, in older Arr4−/− mice, the total cone numbers decreased and cone opsin protein immunoreactive expression levels were significantly reduced, while overall photoreceptor outer nuclear layer thickness was unchanged. Conclusions Our study demonstrates that Arr4−/− mice display distinct phenotypic differences when compared to controls, suggesting that ARR4 modulates essential functions in high acuity vision and downstream cellular signaling pathways that are not fulfilled or substituted by the coexpression of ARR1, despite its high expression levels in all mouse cones. Without normal ARR4 expression levels, cones slowly degenerate with increasing age, making this a new model to study age-related cone dystrophy. PMID:26284544

Highly effective phosphorylation by G protein-coupled receptor kinase 7 of light-activated visual pigment in cones.

PubMed

Tachibanaki, Shuji; Arinobu, Daisuke; Shimauchi-Matsukawa, Yoshie; Tsushima, Sawae; Kawamura, Satoru

2005-06-28

Cone photoreceptors show briefer photoresponses than rod photoreceptors. Our previous study showed that visual pigment phosphorylation, a quenching mechanism of light-activated visual pigment, is much more rapid in cones than in rods. Here, we measured the early time course of this rapid phosphorylation with good time resolution and directly compared it with the photoresponse time course in cones. At the time of photoresponse recovery, almost two phosphates were incorporated into a bleached cone pigment molecule, which indicated that the visual pigment phosphorylation coincides with the photoresponse recovery. The rapid phosphorylation in cones is attributed to very high activity of visual pigment kinase [G protein-coupled receptor kinase (GRK) 7] in cones. Because of this high activity, cone pigment is readily phosphorylated at very high bleach levels, which probably explains why cone photoresponses recover quickly even after a very bright light and do not saturate under intense background light. The high GRK7 activity is brought about by high content of a highly potent enzyme. The expression level of GRK7 was 10 times higher than that of rod kinase (GRK1), and the specific activity of a single GRK7 molecule was approximately 10 times higher than that of GRK1. The specific activity of GRK7 is the highest among the GRKs so far known. Our result seems to explain the response characteristics of cone photoreceptors in many aspects, including the nonsaturation of the cone responses during daylight vision.

Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function.

PubMed

Nishiguchi, Koji M; Friedman, James S; Sandberg, Michael A; Swaroop, Anand; Berson, Eliot L; Dryja, Thaddeus P

2004-12-21

Mice lacking the transcription factor Nrl have no rod photoreceptors and an increased number of short-wavelength-sensitive cones. Missense mutations in NRL are associated with autosomal dominant retinitis pigmentosa; however, the phenotype associated with the loss of NRL function in humans has not been reported. We identified two siblings who carried two allelic mutations: a predicted null allele (L75fs) and a missense mutation (L160P) altering a highly conserved residue in the domain involved in DNA-binding-site recognition. In vitro luciferase reporter assays demonstrated that the NRL-L160P mutant had severely reduced transcriptional activity compared with the WT NRL protein, consistent with a severe loss of function. The affected patients had night blindness since early childhood, consistent with a severe reduction in rod function. Color vision was normal, suggesting the presence of all cone color types; nevertheless, a comparison of central visual fields evaluated with white-on-white and blue-on-yellow light stimuli was consistent with a relatively enhanced function of short-wavelength-sensitive cones in the macula. The fundi had signs of retinal degeneration (such as vascular attenuation) and clusters of large, clumped, pigment deposits in the peripheral fundus at the level of the retinal pigment epithelium (clumped pigmentary retinal degeneration). Our report presents an unusual clinical phenotype in humans with loss-of-function mutations in NRL.

Severe X-linked chondrodysplasia punctata in nine new female fetuses.

PubMed

Lefebvre, Mathilde; Dufernez, Fabienne; Bruel, Ange-Line; Gonzales, Marie; Aral, Bernard; Saint-Onge, Judith; Gigot, Nadège; Desir, Julie; Daelemans, Caroline; Jossic, Frédérique; Schmitt, Sébastien; Mangione, Raphaele; Pelluard, Fanny; Vincent-Delorme, Catherine; Labaune, Jean-Marc; Bigi, Nicole; D'Olne, Dominique; Delezoide, Anne-Lise; Toutain, Annick; Blesson, Sophie; Cormier-Daire, Valérie; Thevenon, Julien; El Chehadeh, Salima; Masurel-Paulet, Alice; Joyé, Nicole; Vibert-Guigue, Claude; Rigonnot, Luc; Rousseau, Thierry; Vabres, Pierre; Hervé, Philippe; Lamazière, Antonin; Rivière, Jean-Baptiste; Faivre, Laurence; Laurent, Nicole; Thauvin-Robinet, Christel

2015-07-01

Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations. © 2015 John Wiley & Sons, Ltd.

Deafferented Adult Rod Bipolar Cells Create New Synapses with Photoreceptors to Restore Vision.

PubMed

Beier, Corinne; Hovhannisyan, Anahit; Weiser, Sydney; Kung, Jennifer; Lee, Seungjun; Lee, Dae Yeong; Huie, Philip; Dalal, Roopa; Palanker, Daniel; Sher, Alexander

2017-04-26

Upon degeneration of photoreceptors in the adult retina, interneurons, including bipolar cells, exhibit a plastic response leading to their aberrant rewiring. Photoreceptor reintroduction has been suggested as a potential approach to sight restoration, but the ability of deafferented bipolar cells to establish functional synapses with photoreceptors is poorly understood. Here we use photocoagulation to selectively destroy photoreceptors in adult rabbits while preserving the inner retina. We find that rods and cones shift into the ablation zone over several weeks, reducing the blind spot at scotopic and photopic luminances. During recovery, rod and cone bipolar cells exhibit markedly different responses to deafferentation. Rod bipolar cells extend their dendrites to form new synapses with healthy photoreceptors outside the lesion, thereby restoring visual function in the deafferented retina. Secretagogin-positive cone bipolar cells did not exhibit such obvious dendritic restructuring. These findings are encouraging to the idea of photoreceptor reintroduction for vision restoration in patients blinded by retinal degeneration. At the same time, they draw attention to the postsynaptic side of photoreceptor reintroduction; various bipolar cell types, representing different visual pathways, vary in their response to the photoreceptor loss and in their consequent dendritic restructuring. SIGNIFICANCE STATEMENT Loss of photoreceptors during retinal degeneration results in permanent visual impairment. Strategies for vision restoration based on the reintroduction of photoreceptors inherently rely on the ability of the remaining retinal neurons to correctly synapse with new photoreceptors. We show that deafferented bipolar cells in the adult mammalian retina can reconnect to rods and cones and restore retinal sensitivity at scotopic and photopic luminances. Rod bipolar cells extend their dendrites to form new synapses with healthy rod photoreceptors. These findings support

Deafferented Adult Rod Bipolar Cells Create New Synapses with Photoreceptors to Restore Vision

PubMed Central

Hovhannisyan, Anahit; Kung, Jennifer; Lee, Seungjun; Lee, Dae Yeong; Huie, Philip; Dalal, Roopa; Palanker, Daniel

2017-01-01

Upon degeneration of photoreceptors in the adult retina, interneurons, including bipolar cells, exhibit a plastic response leading to their aberrant rewiring. Photoreceptor reintroduction has been suggested as a potential approach to sight restoration, but the ability of deafferented bipolar cells to establish functional synapses with photoreceptors is poorly understood. Here we use photocoagulation to selectively destroy photoreceptors in adult rabbits while preserving the inner retina. We find that rods and cones shift into the ablation zone over several weeks, reducing the blind spot at scotopic and photopic luminances. During recovery, rod and cone bipolar cells exhibit markedly different responses to deafferentation. Rod bipolar cells extend their dendrites to form new synapses with healthy photoreceptors outside the lesion, thereby restoring visual function in the deafferented retina. Secretagogin-positive cone bipolar cells did not exhibit such obvious dendritic restructuring. These findings are encouraging to the idea of photoreceptor reintroduction for vision restoration in patients blinded by retinal degeneration. At the same time, they draw attention to the postsynaptic side of photoreceptor reintroduction; various bipolar cell types, representing different visual pathways, vary in their response to the photoreceptor loss and in their consequent dendritic restructuring. SIGNIFICANCE STATEMENT Loss of photoreceptors during retinal degeneration results in permanent visual impairment. Strategies for vision restoration based on the reintroduction of photoreceptors inherently rely on the ability of the remaining retinal neurons to correctly synapse with new photoreceptors. We show that deafferented bipolar cells in the adult mammalian retina can reconnect to rods and cones and restore retinal sensitivity at scotopic and photopic luminances. Rod bipolar cells extend their dendrites to form new synapses with healthy rod photoreceptors. These findings support

Early-Onset, Slow Progression of Cone Photoreceptor Dysfunction and Degeneration in CNG Channel Subunit CNGB3 Deficiency

PubMed Central

Xu, Jianhua; Morris, Lynsie; Fliesler, Steven J.; Sherry, David M.

2011-01-01

Purpose. To investigate the progression of cone dysfunction and degeneration in CNG channel subunit CNGB3 deficiency. Methods. Retinal structure and function in CNGB3−/− and wild-type (WT) mice were evaluated by electroretinography (ERG), lectin cytochemistry, and correlative Western blot analysis of cone-specific proteins. Cone and rod terminal integrity was assessed by electron microscopy and synaptic protein immunohistochemical distribution. Results. Cone ERG amplitudes (photopic b-wave) in CNGB3−/− mice were reduced to approximately 50% of WT levels by postnatal day 15, decreasing further to approximately 30% of WT levels by 1 month and to approximately 20% by 12 months of age. Rod ERG responses (scotopic a-wave) were not affected in CNGB3−/− mice. Average CNGB3−/− cone densities were approximately 80% of WT levels at 1 month and declined slowly thereafter to only approximately 50% of WT levels by 12 months. Expression levels of M-opsin, cone transducin α-subunit, and cone arrestin in CNGB3−/− mice were reduced by 50% to 60% by 1 month and declined to 35% to 45% of WT levels by 9 months. In addition, cone opsin mislocalized to the outer nuclear layer and the outer plexiform layer in the CNGB3−/− retina. Cone and rod synaptic marker expression and terminal ultrastructure were normal in the CNGB3−/− retina. Conclusions. These findings are consistent with an early-onset, slow progression of cone functional defects and cone loss in CNGB3−/− mice, with the cone signaling deficits arising from disrupted phototransduction and cone loss rather than from synaptic defects. PMID:21273547

Outcomes of Corneal Cross-Linking Correlate With Cone-Specific Lysyl Oxidase Expression in Patients With Keratoconus.

PubMed

Shetty, Rohit; Rajiv Kumar, Nimisha; Pahuja, Natasha; Deshmukh, Rashmi; Vunnava, KrishnaPoojita; Abilash, Valsala Gopalakrishnan; Sinha Roy, Abhijit; Ghosh, Arkasubhra

2018-03-01

To evaluate the correlation of visual and keratometry outcomes after corneal cross-linking (CXL) in patients with keratoconus with cone epithelium-specific gene expression levels. Corneal epithelium was obtained from 35 eyes that underwent accelerated CXL (KXLII, 9 mW/cm for 10 min). Using corneal topography, epithelium over the cone and periphery was obtained separately from each subject. The ratio of gene expression for lysyl oxidase (LOX), matrix metalloproteinase 9 (MMP9), bone morphogenic protein 7, tissue inhibitor of metalloproteinase 1, collagen, type I, alpha 1, and collagen, type IV, alpha 1 (COL IVA1) from the cone and peripheral cornea was correlated with the outcome of cross-linking surgery. Patients were assessed for visual acuity, keratometry, refraction, and corneal densitometry before and 6 months after surgery. Based on the change in corneal flattening indicated by ΔKmax, the outcomes were classified as a higher response or lower response. Reduction in keratometric indices correlated with improved spherical equivalent after CXL. Preoperative levels of cone-specific LOX expression in cases with a higher response were significant (P = 0.001). COL IVA1, bone morphogenic protein 7, and tissue inhibitor of metalloproteinase 1 gene expressions were reduced in the cones of the subjects with a lower response. MMP9 levels were relatively lower in cases with a higher response compared with those with a lower response. Our study demonstrates that preoperative levels of molecular factors such as LOX, MMP9, and COL IVA1 aid in understanding CXL outcomes at the tissue level.

Clinical and ERG data in a family with autosomal dominant RP and Pro-347-Arg mutation in the rhodopsin gene.

PubMed

Niemeyer, G; Trüb, P; Schinzel, A; Gal, A

1992-01-01

In a family with autosomal dominant retinitis pigmentosa, documented over six generations, a previously undescribed point mutation in the rhodopsin gene could be identified. The mutation found in the six affected members examined but in none of the controls, including healthy members of the family, was a point mutation in codon 347 predicting a substitution of the amino acid arginine for proline, designated Pro-347-Arg. Six affected members from two generations were examined clinically and with ganzfeld rod and cone electroretinography. The cone and, more dramatically, the rod electroretinograms were reduced to residual b-wave amplitudes or were non-detectable as early as ages 18 to 22 years. The Pro-347-Arg mutation resulted in a subjectively and clinically homogeneous phenotype: early onset of night blindness before age 11, relatively preserved usable visual fields until about age 30, blindness at ages 40 to 60, and change from an initial apparently sine pigmento to a hyperpigmented and atrophic fundus picture between 30 and 50 years of age.

Formation of a pinched electron beam and an intense x-ray source in radial foil rod-pinch diodes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sorokin, S. A.

2016-04-15

Low-impedance rod-pinch diode experiments were performed on the MIG generator at Institute of High Current Electronics using an aluminum foil placed between concentric electrodes of a rod-pinch diode. The J × B force accelerates the foil plasma in the axial and radial directions. After the foil plasma is pushed beyond the tip of the rod, a vacuum gap and a pinched electron beam form. The anode and cathode plasmas expansion and the following plasmas sweeping up by the J × B force can result in repetitive gap formations and closures, which are evident in the several successive intense x-ray pulses. A 0.7-mm-size point-like x-raymore » source was realized using a 1-mm-diameter tungsten rod, tapered to a point over the last 10 mm. The results of experiments show that the foil-shorted rod-pinch diode configuration has the potential to form low-impedance diodes, to shorten x-ray pulse duration and to realize submillimeter spot-size x-ray sources.« less

Activation and quenching of the phototransduction cascade in retinal cones as inferred from electrophysiology and mathematical modeling

PubMed Central

Astakhova, Luba; Firsov, Michael

2015-01-01

Purpose To experimentally identify and quantify factors responsible for the lower sensitivity of retinal cones compared to rods. Methods Electrical responses of frog rods and fish (Carassius) cones to short flashes of light were recorded using the suction pipette technique. A fast solution changer was used to apply a solution that fixed intracellular Ca2+ concentration at the prestimulus level, thereby disabling Ca2+ feedback, to the outer segment (OS). The results were analyzed with a specially designed mathematical model of phototransduction. The model included all basic processes of activation and quenching of the phototransduction cascade but omitted unnecessary mechanistic details of each step. Results Judging from the response versus intensity curves, Carassius cones were two to three orders of magnitude less sensitive than frog rods. There was a large scatter in sensitivity among individual cones, with red-sensitive cones being on average approximately two times less sensitive than green-sensitive ones. The scatter was mostly due to different signal amplification, since the kinetic parameters of the responses among cones were far less variable than sensitivity. We argue that the generally accepted definition of the biochemical amplification in phototransduction cannot be used for comparing amplification in rods and cones, since it depends on an irrelevant factor, that is, the cell’s volume. We also show that the routinely used simplified parabolic curve fitting to an initial phase of the response leads to a few-fold underestimate of the amplification. We suggest a new definition of the amplification that only includes molecular parameters of the cascade activation, and show how it can be derived from experimental data. We found that the mathematical model with unrestrained parameters can yield an excellent fit to experimental responses. However, the fits with wildly different sets of parameters can be virtually indistinguishable, and therefore cannot

Linkage localization of X-linked Charcot-Marie-Tooth disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bergoffen, J.; Trofatter, J.; Haines, J.L.

1993-02-01

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived frommore » work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.« less

A reconstruction method for cone-beam differential x-ray phase-contrast computed tomography.

PubMed

Fu, Jian; Velroyen, Astrid; Tan, Renbo; Zhang, Junwei; Chen, Liyuan; Tapfer, Arne; Bech, Martin; Pfeiffer, Franz

2012-09-10

Most existing differential phase-contrast computed tomography (DPC-CT) approaches are based on three kinds of scanning geometries, described by parallel-beam, fan-beam and cone-beam. Due to the potential of compact imaging systems with magnified spatial resolution, cone-beam DPC-CT has attracted significant interest. In this paper, we report a reconstruction method based on a back-projection filtration (BPF) algorithm for cone-beam DPC-CT. Due to the differential nature of phase contrast projections, the algorithm restrains from differentiation of the projection data prior to back-projection, unlike BPF algorithms commonly used for absorption-based CT data. This work comprises a numerical study of the algorithm and its experimental verification using a dataset measured with a three-grating interferometer and a micro-focus x-ray tube source. Moreover, the numerical simulation and experimental results demonstrate that the proposed method can deal with several classes of truncated cone-beam datasets. We believe that this feature is of particular interest for future medical cone-beam phase-contrast CT imaging applications.

Cone arrestin: deciphering the structure and functions of arrestin 4 in vision.

PubMed

Craft, Cheryl Mae; Deming, Janise D

2014-01-01

Cone arrestin (Arr4) was discovered 20 years ago as a human X-chromosomal gene that is highly expressed in pinealocytes and cone photoreceptors. Subsequently, specific antibodies were developed to identify Arr4 and to distinguish cone photoreceptor morphology in health and disease states. These reagents were used to demonstrate Arr4 translocation from cone inner segments in the dark to outer segments with light stimulation, similarly to Arrestin 1 (Arr1) translocation in rod photoreceptors. A decade later, the Arr4 crystal structure was solved, which provided more clues about Arr4's mechanisms of action. With the creation of genetically engineered visual arrestin knockout mice, one critical function of Arr4 was clarified. In single living cones, both visual arrestins bind to light-activated, G protein receptor kinase 1 (Grk1) phosphorylated cone opsins to desensitize them, and in their absence, mouse cone pigment shutoff is delayed. Still under investigation are additional functions; however, it is clear that Arr4 has non-opsin-binding partners and diverse synaptic roles, including cellular anchoring and trafficking. Recent studies reveal Arr4 is involved in high temporal resolution and contrast sensitivity, which opens up a new direction for research on this intriguing protein. Even more exciting is the potential for therapeutic use of the Arr4 promoter with an AAV-halorhodopsin that was shown to be effective in using the remaining cones in retinal degeneration mouse models to drive inner retinal circuitry for motion detection and light/dark discrimination.

Crossflow between subchannels in a 5 x 5 rod-bundle geometry

NASA Astrophysics Data System (ADS)

Lee, Jungjin; Park, Hyungmin

2017-11-01

In the present study, we experimentally investigate the single-phase (water as a working fluid) flow in a vertical 5 x 5 rod-bundle geometry using a particle image velociemtry, especially focusing on the crossflow phenomena between subchannels. This crossflow phenomena is very important in determining the performance and safety of nuclear power plant. To measure the flow behind the rod, it is made of FEP (Fluorinated Ethylene Propylene) to achieve the index matching. The ratio of pitch between rods and rod diameter is 1.4, and the considered Reynolds number based on a hydraulic diameter of a channel and an axial bulk velocity is 10000. Also, the typical grid spacer is installed periodically along the streamwise direction. Depending on the location of subchannel (e.g., distance to the side wall or grid spacer), the flow (turbulence) statistics show large variations that will be discussed in detail. Furthermore, we will suggest a modified crossflow model that can explain the varying crossflow phenomena more clearly. Supported by NRF Grant (NRF-2016M2B2A9A02945068) of the Korean government.

Depletion of calcium stores regulates calcium influx and signal transmission in rod photoreceptors

PubMed Central

Szikra, Tamas; Cusato, Karen; Thoreson, Wallace B; Barabas, Peter; Bartoletti, Theodore M; Krizaj, David

2008-01-01

Tonic synapses are specialized for sustained calcium entry and transmitter release, allowing them to operate in a graded fashion over a wide dynamic range. We identified a novel plasma membrane calcium entry mechanism that extends the range of rod photoreceptor signalling into light-adapted conditions. The mechanism, which shares molecular and physiological characteristics with store-operated calcium entry (SOCE), is required to maintain baseline [Ca2+]i in rod inner segments and synaptic terminals. Sustained Ca2+ entry into rod cytosol is augmented by store depletion, blocked by La3+ and Gd3+ and suppressed by organic antagonists MRS-1845 and SKF-96365. Store depletion and the subsequent Ca2+ influx directly stimulated exocytosis in terminals of light-adapted rods loaded with the activity-dependent dye FM1–43. Moreover, SOCE blockers suppressed rod-mediated synaptic inputs to horizontal cells without affecting presynaptic voltage-operated Ca2+ entry. Silencing of TRPC1 expression with small interference RNA disrupted SOCE in rods, but had no effect on cone Ca2+ signalling. Rods were immunopositive for TRPC1 whereas cone inner segments immunostained with TRPC6 channel antibodies. Thus, SOCE modulates Ca2+ homeostasis and light-evoked neurotransmission at the rod photoreceptor synapse mediated by TRPC1. PMID:18755743

X-ray cone-beam computed tomography: principles, applications, challenges and solutions

NASA Astrophysics Data System (ADS)

Noo, Frederic

2010-03-01

In the nineties, x-ray computed tomography, commonly referred to as CT, seemed to be on the track to become old technology, bound to be replaced by more sophisticated techniques such as magnetic resonance imaging, due in particular to the harmful effects of x-ray radiation exposure. Yet, the new century brought with it new technology that allowed a complete change in trends and re-affirmed CT as an essential tool in radiology. For instance, the popularity of CT in 2007 was such that approximately 68.7 million CT examinations were performed in the United States, which was nearly 2.5 times the number of magnetic resonance (MRI) examinations. More than that, CT has expanded beyond its conventional diagnostic role; CT is now used routinely in interventional radiology and also in radiation therapy treatment. The technology advances that allowed the revival of CT are those that made fast, accurate cone-beam data acquisition possible. Nowadays, cone-beam data acquisition allows scanning large volumes with isotropic sub-millimeter spatial resolution in a very fast time, which can be as short as 500ms for cardiac imaging. The principles of cone-beam imaging will be first reviewed. Then a discussion of its applications will be given. Old and new challenges will be presented along the way with current solutions.

Genomic evidence for rod monochromacy in sloths and armadillos suggests early subterranean history for Xenarthra

PubMed Central

Emerling, Christopher A.; Springer, Mark S.

2015-01-01

Rod monochromacy is a rare condition in vertebrates characterized by the absence of cone photoreceptor cells. The resulting phenotype is colourblindness and low acuity vision in dim-light and blindness in bright-light conditions. Early reports of xenarthrans (armadillos, sloths and anteaters) suggest that they are rod monochromats, but this has not been tested with genomic data. We searched the genomes of Dasypus novemcinctus (nine-banded armadillo), Choloepus hoffmanni (Hoffmann's two-toed sloth) and Mylodon darwinii (extinct ground sloth) for retinal photoreceptor genes and examined them for inactivating mutations. We performed PCR and Sanger sequencing on cone phototransduction genes of 10 additional xenarthrans to test for shared inactivating mutations and estimated the timing of inactivation for photoreceptor pseudogenes. We concluded that a stem xenarthran became an long-wavelength sensitive-cone monochromat following a missense mutation at a critical residue in SWS1, and a stem cingulate (armadillos, glyptodonts and pampatheres) and stem pilosan (sloths and anteaters) independently acquired rod monochromacy early in their evolutionary history following the inactivation of LWS and PDE6C, respectively. We hypothesize that rod monochromacy in armadillos and pilosans evolved as an adaptation to a subterranean habitat in the early history of Xenarthra. The presence of rod monochromacy has major implications for understanding xenarthran behavioural ecology and evolution. PMID:25540280

Sequential pictorial presentation of neural interaction in the retina. 2. The depolarizing and hyperpolarizing bipolar cells at rod terminals.

PubMed

Sjöstrand, F S

2002-01-01

Each rod is connected to one depolarizing and one hyperpolarizing bipolar cell. The synaptic connections of cone processes to each bipolar cell and presynaptically to the two rod-bipolar cell synapses establishes conditions for lateral interaction at this level. Thus, the cones raise the threshold for bipolar cell depolarization which is the basis for spatial brightness contrast enhancement and consequently for high visual acuity (Sjöstrand, 2001a). The cones facilitate ganglion cell depolarization by the bipolar cells and cone input prevents horizontal cell blocking of depolarization of the depolarizing bipolar cell, extending rod vision to low illumination. The combination of reduced cone input and transient hyperpolarization of the hyperpolarizing bipolar cell at onset of a light stimulus facilitates ganglion cell depolarization extensively at onset of the stimulus while no corresponding enhancement applies to the ganglion cell response at cessation of the stimulus, possibly establishing conditions for discrimination between on- vs. off-signals in the visual centre. Reduced cone input and hyperpolarization of the hyperpolarizing bipolar cell at onset of a light stimulus accounts for Granit's (1941) 'preexcitatory inhibition'. Presynaptic inhibition maintains transmitter concentration low in the synaptic gap at rod-bipolar cell and bipolar cell-ganglion cell synapses, securing proportional and amplified postsynaptic responses at these synapses. Perfect timing of variations in facilitatory and inhibitory input to the ganglion cell confines the duration of ganglion cell depolarization at onset and at cessation of a light stimulus to that of a single synaptic transmission.

A multi-cone x-ray imaging Bragg crystal spectrometer

DOE PAGES

Bitter, M.; Hill, K. W.; Gao, Lan; ...

2016-08-26

This article describes a new x-ray imaging Bragg crystal spectrometer, which—in combination with a streak camera or a gated strip detector—can be used for time-resolved measurements of x-ray line spectra at the National Ignition Facility and other high power laser facilities. The main advantage of this instrument is that it produces perfect images of a point source for each wavelength in a selectable spectral range and that the detector plane can be perpendicular to the crystal surface or inclined by an arbitrary angle with respect to the crystal surface. Furthermore, these unique imaging properties are obtained by bending the x-raymore » diffracting crystal into a certain shape, which is generated by arranging multiple cones with different aperture angles on a common nodal line.« less

Cone-like rhodopsin expressed in the all-cone retina of the colubrid pine snake as a potential adaptation to diurnality.

PubMed

Bhattacharyya, Nihar; Darren, Benedict; Schott, Ryan K; Tropepe, Vincent; Chang, Belinda S W

2017-07-01

Colubridae is the largest and most diverse family of snakes, with visual systems that reflect this diversity, encompassing a variety of retinal photoreceptor organizations. The transmutation theory proposed by Walls postulates that photoreceptors could evolutionarily transition between cell types in squamates, but few studies have tested this theory. Recently, evidence for transmutation and rod-like machinery in an all-cone retina has been identified in a diurnal garter snake ( Thamnophis ), and it appears that the rhodopsin gene at least may be widespread among colubrid snakes. However, functional evidence supporting transmutation beyond the existence of the rhodopsin gene remains rare. We examined the all-cone retina of another colubrid, Pituophis melanoleucus , thought to be more secretive/burrowing than Thamnophis We found that P. melanoleucus expresses two cone opsins (SWS1, LWS) and rhodopsin (RH1) within the eye. Immunohistochemistry localized rhodopsin to the outer segment of photoreceptors in the all-cone retina of the snake and all opsin genes produced functional visual pigments when expressed in vitro Consistent with other studies, we found that P. melanoleucus rhodopsin is extremely blue-shifted. Surprisingly, P. melanoleucus rhodopsin reacted with hydroxylamine, a typical cone opsin characteristic. These results support the idea that the rhodopsin-containing photoreceptors of P. melanoleucus are the products of evolutionary transmutation from rod ancestors, and suggest that this phenomenon may be widespread in colubrid snakes. We hypothesize that transmutation may be an adaptation for diurnal, brighter-light vision, which could result in increased spectral sensitivity and chromatic discrimination with the potential for colour vision. © 2017. Published by The Company of Biologists Ltd.

X-ray Synchrotron Microtomography of a silicified Jurassic Cheirolepidiaceae (Conifer) cone: histology and morphology of Pararaucaria collinsonae sp. nov.

PubMed Central

Steart, David C.; Spencer, Alan R.T.; Garwood, Russell J.; Hilton, Jason; Munt, Martin C.; Needham, John

2014-01-01

We document a new species of ovulate cone (Pararaucaria collinsonae) on the basis of silicified fossils from the Late Jurassic Purbeck Limestone Group of southern England (Tithonian Stage: ca. 145 million years). Our description principally relies on the anatomy of the ovuliferous scales, revealed through X-ray synchrotron microtomography (SRXMT) performed at the Diamond Light Source (UK). This study represents the first application of SRXMT to macro-scale silicified plant fossils, and demonstrates the significant advantages of this approach, which can resolve cellular structure over lab-based X-ray computed microtomography (XMT). The method enabled us to characterize tissues and precisely demarcate their boundaries, elucidating organ shape, and thus allowing an accurate assessment of affinities. The cones are broadly spherical (ca. 1.3 cm diameter), and are structured around a central axis with helically arranged bract/scale complexes, each of which bares a single ovule. A three-lobed ovuliferous scale and ovules enclosed within pocket-forming tissue, demonstrate an affinity with Cheirolepidiaceae. Details of vascular sclerenchyma bundles, integument structure, and the number and attachment of the ovules indicate greatest similarity to P. patagonica and P. carrii. This fossil develops our understanding of the dominant tree element of the Purbeck Fossil Forest, providing the first evidence for ovulate cheirolepidiaceous cones in Europe. Alongside recent discoveries in North America, this significantly extends the known palaeogeographic range of Pararaucaria, supporting a mid-palaeolatitudinal distribution in both Gondwana and Laurasia during the Late Jurassic. Palaeoclimatic interpretations derived from contemporaneous floras, climate sensitive sediments, and general circulation climate models indicate that Pararaucaria was a constituent of low diversity floras in semi-arid Mediterranean-type environments. PMID:25374776

Formation of Sub-Millimeter-Size Powerful X-Ray Sources in Low-Impedance Rod-Pinch Diodes

NASA Astrophysics Data System (ADS)

Sorokin, S. A.

2018-01-01

In the paper, experiments on the formation of a low-impedance diode and a focused electron beam as a result of detachment of radial wires, accelerated by the current of a high-current generator, from the rod anode have been described. In the experiments, along with studies of conditions for compact focusing of the electron beam and effective generation of hard x-rays, the shape of the tip of the anode rod is determined at which the x-ray source is point-sized when viewed in the radial direction.

Genetics Home Reference: X-linked thrombocytopenia

MedlinePlus

... Facebook Twitter Home Health Conditions X-linked thrombocytopenia X-linked thrombocytopenia Printable PDF Open All Close All ... Javascript to view the expand/collapse boxes. Description X-linked thrombocytopenia is a bleeding disorder that primarily ...

Editorial: X-chromosome-linked Kallmann's syndrome: Pathology at the molecular level

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prager, D.; Braunstein, G.D.

Kallmann's syndrome or olfactogenital dysplasia refers to a disorder characterized by hypogonadotropic hypogonadism and anosmia or hyposmia which can occur sporadically or in a familial setting. Originally described in 1856, the first familial cases were reported by Kallmann et al., in 1944. Based on segregation analysis of multiple families, three modes of transmission have been documented: X-linked, autosomal dominant with variable penetrance, and autosomal recessive. Kallmann's syndrome occurs in less than 1 in 10,000 male births, with a 5-fold excess of affected males to females, suggesting that the X-linked form is the most frequent. By genetic linkage analysis the X-linkedmore » form of Kallmann's syndrome was localized to Xp22.3. This was confirmed by the description of patients with contiguous gene syndromes due to deletions of various portions of the distal short arm of the X-chromosome. Such patients present with complex phenotypes characterized by a combination of Kallmann's syndrome with X-linked icthyosis due to steroid sulfatase deficiency, chondrodysplasia punctata, short stature, and mental retardation. DNA analysis has identified and mapped the genes responsible for these disorders. 10 refs., 1 fig., 1 tab.« less

A bright attosecond x-ray pulse train generation in a double-laser-driven cone target

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Li-Xiang; Yu, Tong-Pu, E-mail: tongpu@nudt.edu.cn; Shao, Fu-Qiu

By using full three-dimensional particle-in-cell and Monte Carlo simulations, we investigate the generation of a high-brightness attosecond x-ray pulse train in a double-laser-driven cone target. The scheme makes use of two lasers: the first high-intensity laser with a laser peak intensity 1.37 × 10{sup 20 }W/cm{sup 2} irradiates the cone and produces overdense attosecond electron bunches; the second counterpropagating weakly relativistic laser with a laser peak intensity 4.932 × 10{sup 17 }W/cm{sup 2} interacts with the produced electron bunches and a bright x-ray pulse train is generated by Thomson backscattering of the second laser off the attosecond electron bunches. It is shown that the photon fluxmore » rises by 5 times using the cone target as compared with a normal channel. Meanwhile, the x-ray peak brightness increases significantly from 1.4 × 10{sup 21}/(s mm{sup 2} mrad{sup 2} 0.1 keV) to 6.0 × 10{sup 21}/(s mm{sup 2} mrad{sup 2} 0.1 keV), which is much higher than that of the Thomson x-ray source generated from traditional accelerators. We also discuss the influence of the laser and target parameters on the x-ray pulse properties. This compact bright x-ray source may have diverse applications, e.g., the study of electric dynamics and harmonics emission in the atomic scale.« less

Homeobox genes and melatonin synthesis: regulatory roles of the cone-rod homeobox transcription factor in the rodent pineal gland.

PubMed

Rohde, Kristian; Møller, Morten; Rath, Martin Fredensborg

2014-01-01

Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT) enzyme activity. In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction of Aanat transcription. However, additional transcriptional control mechanisms exist. Homeobox genes, which are generally known to encode transcription factors controlling developmental processes, are also expressed in the mature rodent pineal gland. Among these, the cone-rod homeobox (CRX) transcription factor is believed to control pineal-specific Aanat expression. Based on recent advances in our understanding of Crx in the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specific Aanat expression and by facilitating cAMP response element-based circadian melatonin production.

Homeobox Genes and Melatonin Synthesis: Regulatory Roles of the Cone-Rod Homeobox Transcription Factor in the Rodent Pineal Gland

PubMed Central

Rath, Martin Fredensborg

2014-01-01

Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT) enzyme activity. In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction of Aanat transcription. However, additional transcriptional control mechanisms exist. Homeobox genes, which are generally known to encode transcription factors controlling developmental processes, are also expressed in the mature rodent pineal gland. Among these, the cone-rod homeobox (CRX) transcription factor is believed to control pineal-specific Aanat expression. Based on recent advances in our understanding of Crx in the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specific Aanat expression and by facilitating cAMP response element-based circadian melatonin production. PMID:24877149

Store-operated channels regulate intracellular calcium in mammalian rods

PubMed Central

Molnar, Tünde; Barabas, Peter; Birnbaumer, Lutz; Punzo, Claudio; Kefalov, Vladimir; Križaj, David

2012-01-01

Exposure to daylight closes cyclic nucleotide-gated (CNG) and voltage-operated Ca2+-permeable channels in mammalian rods. The consequent lowering of the cytosolic calcium concentration ([Ca2+]i), if protracted, can contribute to light-induced damage and apoptosis in these cells. We here report that mouse rods are protected against prolonged lowering of [Ca2+]i by store-operated Ca2+ entry (SOCE). Ca2+ stores were depleted in Ca2+-free saline supplemented with the endoplasmic reticulum (ER) sequestration blocker cyclopiazonic acid. Store depletion elicited [Ca2+]i signals that exceeded baseline [Ca2+]i by 5.9 ± 0.7-fold and were antagonized by an inhibitory cocktail containing 2-APB, SKF 96365 and Gd3+. Cation influx through SOCE channels was sufficient to elicit a secondary activation of L-type voltage-operated Ca2+ entry. We also found that TRPC1, the type 1 canonical mammalian homologue of the Drosophila photoreceptor TRP channel, is predominantly expressed within the outer nuclear layer of the retina. Rod loss in Pde6brd1 (rd1), Chx10/Kip1−/−rd1 and Elovl4TG2 dystrophic models was associated with ∼70% reduction in Trpc1 mRNA content whereas Trpc1 mRNA levels in rodless cone-full Nrl−/− retinas were decreased by ∼50%. Genetic ablation of TRPC1 channels, however, had no effect on SOCE, the sensitivity of the rod phototransduction cascade or synaptic transmission at rod and cone synapses. Thus, we localized two new mechanisms, SOCE and TRPC1, to mammalian rods and characterized the contribution of SOCE to Ca2+ homeostasis. By preventing the cytosolic [Ca2+]i from dropping too low under sustained saturating light conditions, these signalling pathways may protect Ca2+-dependent mechanisms within the ER and the cytosol without affecting normal rod function. PMID:22674725

Successful Gene Therapy in the RPGRIP1-deficient Dog: a Large Model of Cone–Rod Dystrophy

PubMed Central

Lhériteau, Elsa; Petit, Lolita; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Libeau, Lyse; Mendes-Madeira, Alexandra; Guihal, Caroline; François, Achille; Guyon, Richard; Provost, Nathalie; Lemoine, Françoise; Papal, Samantha; El-Amraoui, Aziz; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

2014-01-01

For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod–cone dystrophies but not in large models of progressive cone–rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone–rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18–72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22–29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone–rod dystrophy provides great promise for human treatment. PMID:24091916

Convergent synthesis of multiporphyrin light-harvesting rods

DOEpatents

Lindsey, Jonathan S.; Loewe, Robert S.

2003-08-05

The present invention provides a convergent method for the synthesis of light harvesting rods. The rods are oligomers of the formula A.sup.1 (A.sup.b+1).sub.b, wherein b is at least 1, A.sup.1 through A.sup.b+1 are covalently coupled rod segments, and each rod segment A.sup.1 through A.sup.1+b comprises a compound of the formula X.sup.1 (X.sup.m+1).sub.m wherein m is at least 1 and X.sup.1 through X.sup.m+1 are covalently coupled porphyrinic macrocycles. Light harvesting arrays and solar cells containing such light harvesting rods are also described, along with intermediates useful in such methods and rods produced by such methods.

ZIRCONIA RODS FOR COATING ARTICLES BY FLAME SPRAYING

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

1960-04-21

An improved ZrO/sub 2/ rod for flame spraying guns is described which consists of a sintered ZrO/sub 2/ rod of mostly cubic and tetragonal crystals and has a porosity of 8% to 40% by volume. These rods are prepared by mixing 100 parts of ZrO/sub 2/ 75 parts fused, stabilized, 216 mu size, containing 5% CaO, 15 parts fused, stabilized, 25 to 50 mu size, with 5% CaO, 10 parts fused, unstabilized lime-free with 17 parts water, 1 part dextrine, 2 parts corn starch, and extruding. They are then dried and fired in a kiln heated to cone 35 Orton.more » (T.R.H.)« less

Nanocerium oxide increases the survival of adult rod and cone photoreceptor in culture by abrogating hydrogen peroxide-induced oxidative stress.

PubMed

Bhargava, Neelima; Shanmugaiah, Vellasamy; Saxena, Manav; Sharma, Manish; Sethy, Niroj Kumar; Singh, Sushil Kumar; Balakrishnan, Karuppiah; Bhargava, Kalpana; Das, Mainak

2016-09-16

In vitro cell culture system for adult rod and cone photoreceptor (PR) is an effective and economical model for screening drug candidates against all kinds of age related retinal blindness. Interestingly, adult PR cells have a limited survival in the culture system, thus preventing full exploitation of this in vitro approach for drug screening applications. The limited survival of the adult PR cells in culture is due to their inherently high oxidative stress and photic injury. Mixed valence-state ceria nanoparticles have the ability to scavenge free radicals and reduce oxidative stress. Here, ceria nanoparticles of 5-10 nm dimensions have been synthesized, possessing dual oxidation state (+3 and +4) as evident from x-ray photoelectron spectroscopy and exhibiting real time reduction of hydrogen peroxide (H 2 O 2 ) as quantified by absorbance spectroscopy and cyclic voltammogram analysis. Using flow cytometry and cell culture assay, it has been shown that, upon one time addition of 10 nM of nanoceria in the PR culture of the 18 months old adult common carp (Cyprinus carpio) at the time of plating the cells, the oxidative stress caused due to hydrogen peroxide assault could be abrogated. A further single application of nanoceria significantly increases the survival of these fragile cells in the culture, thus paving way for developing a more robust photoreceptor culture model to study the aging photoreceptor cells in a defined condition.

Excitation-resolved cone-beam x-ray luminescence tomography.

PubMed

Liu, Xin; Liao, Qimei; Wang, Hongkai; Yan, Zhuangzhi

2015-07-01

Cone-beam x-ray luminescence computed tomography (CB-XLCT), as an emerging imaging technique, plays an important role in in vivo small animal imaging studies. However, CB-XLCT suffers from low-spatial resolution due to the ill-posed nature of reconstruction. We improve the imaging performance of CB-XLCT by using a multiband excitation-resolved imaging scheme combined with principal component analysis. To evaluate the performance of the proposed method, the physical phantom experiment is performed with a custom-made XLCT/XCT imaging system. The experimental results validate the feasibility of the method, where two adjacent nanophosphors (with an edge-to-edge distance of 2.4 mm) can be located.

Mutations of the Mitochondrial Holocytochrome c–Type Synthase in X-Linked Dominant Microphthalmia with Linear Skin Defects Syndrome

PubMed Central

Wimplinger, Isabella; Morleo, Manuela; Rosenberger, Georg; Iaconis, Daniela; Orth, Ulrike; Meinecke, Peter; Lerer, Israela; Ballabio, Andrea; Gal, Andreas; Franco, Brunella; Kutsche, Kerstin

2006-01-01

The microphthalmia with linear skin defects syndrome (MLS, or MIDAS) is an X-linked dominant male-lethal disorder almost invariably associated with segmental monosomy of the Xp22 region. In two female patients, from two families, with MLS and a normal karyotype, we identified heterozygous de novo point mutations—a missense mutation (p.R217C) and a nonsense mutation (p.R197X)—in the HCCS gene. HCCS encodes the mitochondrial holocytochrome c–type synthase that functions as heme lyase by covalently adding the prosthetic heme group to both apocytochrome c and c1. We investigated a third family, displaying phenotypic variability, in which the mother and two of her daughters carry an 8.6-kb submicroscopic deletion encompassing part of the HCCS gene. Functional analysis demonstrates that both mutant proteins (R217C and Δ197–268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS. Moreover, ectopically expressed HCCS wild-type and the R217C mutant protein are targeted to mitochondria in CHO-K1 cells, whereas the C-terminal–truncated Δ197–268 mutant failed to be sorted to mitochondria. Cytochrome c, the final product of holocytochrome c–type synthase activity, is implicated in both oxidative phosphorylation (OXPHOS) and apoptosis. We hypothesize that the inability of HCCS-deficient cells to undergo cytochrome c–mediated apoptosis may push cell death toward necrosis that gives rise to severe deterioration of the affected tissues. In summary, we suggest that disturbance of both OXPHOS and the balance between apoptosis and necrosis, as well as the X-inactivation pattern, may contribute to the variable phenotype observed in patients with MLS. PMID:17033964

Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

PubMed

Bichet, Daniel G; Bockenhauer, Detlef

2016-03-01

Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cone-beam x-ray luminescence computed tomography based on x-ray absorption dosage

NASA Astrophysics Data System (ADS)

Liu, Tianshuai; Rong, Junyan; Gao, Peng; Zhang, Wenli; Liu, Wenlei; Zhang, Yuanke; Lu, Hongbing

2018-02-01

With the advances of x-ray excitable nanophosphors, x-ray luminescence computed tomography (XLCT) has become a promising hybrid imaging modality. In particular, a cone-beam XLCT (CB-XLCT) system has demonstrated its potential in in vivo imaging with the advantage of fast imaging speed over other XLCT systems. Currently, the imaging models of most XLCT systems assume that nanophosphors emit light based on the intensity distribution of x-ray within the object, not completely reflecting the nature of the x-ray excitation process. To improve the imaging quality of CB-XLCT, an imaging model that adopts an excitation model of nanophosphors based on x-ray absorption dosage is proposed in this study. To solve the ill-posed inverse problem, a reconstruction algorithm that combines the adaptive Tikhonov regularization method with the imaging model is implemented for CB-XLCT reconstruction. Numerical simulations and phantom experiments indicate that compared with the traditional forward model based on x-ray intensity, the proposed dose-based model could improve the image quality of CB-XLCT significantly in terms of target shape, localization accuracy, and image contrast. In addition, the proposed model behaves better in distinguishing closer targets, demonstrating its advantage in improving spatial resolution.

Cone-beam x-ray luminescence computed tomography based on x-ray absorption dosage.

PubMed

Liu, Tianshuai; Rong, Junyan; Gao, Peng; Zhang, Wenli; Liu, Wenlei; Zhang, Yuanke; Lu, Hongbing

2018-02-01

With the advances of x-ray excitable nanophosphors, x-ray luminescence computed tomography (XLCT) has become a promising hybrid imaging modality. In particular, a cone-beam XLCT (CB-XLCT) system has demonstrated its potential in in vivo imaging with the advantage of fast imaging speed over other XLCT systems. Currently, the imaging models of most XLCT systems assume that nanophosphors emit light based on the intensity distribution of x-ray within the object, not completely reflecting the nature of the x-ray excitation process. To improve the imaging quality of CB-XLCT, an imaging model that adopts an excitation model of nanophosphors based on x-ray absorption dosage is proposed in this study. To solve the ill-posed inverse problem, a reconstruction algorithm that combines the adaptive Tikhonov regularization method with the imaging model is implemented for CB-XLCT reconstruction. Numerical simulations and phantom experiments indicate that compared with the traditional forward model based on x-ray intensity, the proposed dose-based model could improve the image quality of CB-XLCT significantly in terms of target shape, localization accuracy, and image contrast. In addition, the proposed model behaves better in distinguishing closer targets, demonstrating its advantage in improving spatial resolution. (2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.

PubMed

Kubota, Daiki; Gocho, Kiyoko; Kikuchi, Sachiko; Akeo, Keiichiro; Miura, Masahiro; Yamaki, Kunihiko; Takahashi, Hiroshi; Kameya, Shuhei

2018-05-02

CEP250 encodes the C-Nap1 protein which belongs to the CEP family of proteins. C-Nap1 has been reported to be expressed in the photoreceptor cilia and is known to interact with other ciliary proteins. Mutations of CEP250 cause atypical Usher syndrome which is characterized by early-onset sensorineural hearing loss (SNHL) and a relatively mild retinitis pigmentosa. This study tested the hypothesis that the mild cone-rod dystrophy (CRD) and SNHL in a non-consanguineous Japanese family was caused by CEP250 mutations. Detailed ophthalmic and auditory examinations were performed on the proband and her family members. Whole exome sequencing (WES) was used on the DNA obtained from the proband. Electrophysiological analysis revealed a mild CRD in two family members. Adaptive optics (AO) imaging showed reduced cone density around the fovea. Auditory examinations showed a slight SNHL in both patients. WES of the proband identified compound heterozygous variants c.361C>T, p.R121*, and c.562C>T, p.R188* in CEP250. The variants were found to co-segregate with the disease in five members of the family. The variants of CEP250 are both null variants and according to American College of Medical Genetics and Genomics (ACMG) standards and guideline, these variants are classified into the very strong category (PVS1). The criteria for both alleles will be pathogenic. Our data indicate that mutations of CEP250 can cause mild CRD and SNHL in Japanese patients. Because the ophthalmological phenotypes were very mild, high-resolution retinal imaging analysis, such as AO, will be helpful in diagnosing CEP250-associated disease.

Genetics Home Reference: X-linked dilated cardiomyopathy

MedlinePlus

... Twitter Home Health Conditions X-linked dilated cardiomyopathy X-linked dilated cardiomyopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked dilated cardiomyopathy is a form of heart ...

Genetics Home Reference: X-linked myotubular myopathy

MedlinePlus

... Twitter Home Health Conditions X-linked myotubular myopathy X-linked myotubular myopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked myotubular myopathy is a condition that primarily ...

Genetics Home Reference: X-linked sideroblastic anemia

MedlinePlus

... Twitter Home Health Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia is an inherited disorder that ...

A longitudinal study of visual function in carriers of X-linked recessive retinitis pigmentosa.

PubMed

Grover, S; Fishman, G A; Anderson, R J; Lindeman, M

2000-02-01

This study was carried out to evaluate the progression of visual function impairment in carriers of X-linked recessive retinitis pigmentosa. We also assessed the relationship between the retinal findings at presentation and the extent of deterioration. Observational, retrospective, case series. Twenty-seven carriers of X-linked recessive retinitis pigmentosa. Each carrier was clinically categorized into one of four grades (grades 0 through 3) depending on the presence or absence of a tapetal-like retinal reflex and the extent of peripheral pigmentary degeneration. A complete ophthalmologic examination was performed and data for visual acuity, visual field area, and electroretinographic measurements were collected on the most recent visit in both eyes. These were then compared with similar data obtained on their initial visits. A comparison of visual function was carried out between the initial visit and the most recent visit on each carrier. The visual acuity was measured with Snellen's acuity charts. The visual fields to targets V-4-e and II-4-e were planimeterized and used for the analysis. The electroretinographic (ERG) measures used were light-adapted single-flash b-wave amplitudes and 30-Hz red flicker for cone function, dark-adapted maximal b-wave amplitudes, and response to a low intensity blue-flash for rod function. None of the 11 carriers with a tapetal-like reflex only (grade 1) showed any significant change in visual acuity or fields as compared with 3 of 7 (43%) carriers with diffuse peripheral pigmentary findings (grade 3) who showed significant deterioration in visual acuity in at least one eye, and 6 of 7 (86%) who showed a significant decrease in visual field area with at least one target size in at least one eye. By comparison, only 1 of 10 carriers with a grade 1 fundus finding demonstrated a significant decrease in maximal dark-adapted ERG function as compared with 5 of 6 (83%) carriers with grade 3 in response to a single-flash stimulus and

Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa

PubMed Central

Murakami, Y; Ikeda, Y; Nakatake, S; Tachibana, T; Fujiwara, K; Yoshida, N; Notomi, S; Nakao, S; Hisatomi, T; Miller, J W; Vavvas, DG; Sonoda, KH; Ishibashi, T

2015-01-01

Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP. PMID:27551484

Bone marrow–derived stem cells preserve cone vision in retinitis pigmentosa

PubMed Central

Smith, Lois E.H.

2004-01-01

Retinitis pigmentosa is a heritable group of blinding diseases resulting from loss of photoreceptors, primarily rods and secondarily cones, that mediate central vision. Loss of retinal vasculature is a presumed metabolic consequence of photoreceptor degeneration. A new study shows that autologous bone marrow–derived lineage-negative hematopoietic stem cells, which incorporate into the degenerating blood vessels in two murine models of retinitis pigmentosa, rd1 and rd10, prevent cone loss. The use of autologous bone marrow might avoid problems with rejection while preserving central cone vision in a wide variety of genetically disparate retinal degenerative diseases. PMID:15372096

ES1 is a mitochondrial enlarging factor contributing to form mega-mitochondria in zebrafish cones.

PubMed

Masuda, Takamasa; Wada, Yasutaka; Kawamura, Satoru

2016-03-01

Total mass of mitochondria increases during cell proliferation and differentiation through mitochondrial biogenesis, which includes mitochondrial proliferation and growth. During the mitochondrial growth, individual mitochondria have been considered to be enlarged independently of mitochondrial fusion. However, molecular basis for this enlarging process has been poorly understood. Cone photoreceptor cells in the retina possess large mitochondria, so-called mega-mitochondria that have been considered to arise via the enlarging process. Here we show that ES1 is a novel mitochondria-enlarging factor contributing to form mega-mitochondria in cones. ES1 is specifically expressed in cones and localized to mitochondria including mega-mitochondria. Knockdown of ES1 markedly reduced the mitochondrial size in cones. In contrast, ectopic expression of ES1 in rods significantly increased both the size of individual mitochondria and the total mass of the mitochondrial cluster without changing the number of them. RNA-seq analysis showed that ERRα and its downstream mitochondrial genes were significantly up-regulated in the ES1-expressing rods, suggesting facilitation of mitochondrial enlargement via ERRα-dependent processes. Furthermore, higher energy state was detected in the ES1-expressing rods, indicating that the enlarged mitochondria by ES1 are capable of producing high energy. ES1 is the mitochondrial protein that is first found to promote enlargement of individual mitochondria.

Mouse Cone Photoreceptors Co-express Two Functional Visual Arrestins

PubMed Central

Nikonov, Sergei S.; Brown, Bruce M.; Davis, Jason A.; Zuniga, Freddi I.; Bragin, Alvina; Pugh, Edward N.; Craft, Cheryl M.

2008-01-01

Arrestins are members of a superfamily of proteins that arrest the activity of G-protein coupled receptors. Mouse cone photoreceptors express two visual arrestins, Arr1 and Arr4 (Carr). We quantified their expression levels and subcellular distributions in mouse cones: total Arr1 was estimated to be in an ~ 6:1 ratio to cone opsin, about 50-fold higher than Arr4. Recordings from single cones of Arr1−/− and Arr4−/− mice establish that both proteins are competent to arrest the activity of photoactivated S- and M- cone opsins. Recordings from Arr1−/− , Arr4−/− double-knockout mice establish a requirement for at least one of the two visual arrestins for normal cone opsin inactivation at all flash intensities. These recordings also reveal low activity photoproducts of S- and M-opsins that are absent when Grk1 and an arrestin are co-expressed, but which decay 70-fold more rapidly than the comparable photoproducts of rhodopsin in rods. PMID:18701071

Direct interaction of the inhibitory gamma-subunit of Rod cGMP phosphodiesterase (PDE6) with the PDE6 GAFa domains.

PubMed

Muradov, Khakim G; Granovsky, Alexey E; Schey, Kevin L; Artemyev, Nikolai O

2002-03-26

Retinal rod and cone cGMP phosphodiesterases (PDE6 family) function as the effector enzyme in the vertebrate visual transduction cascade. The activity of PDE6 catalytic subunits is controlled by the Pgamma-subunits. In addition to the inhibition of cGMP hydrolysis at the catalytic sites, Pgamma is known to stimulate a noncatalytic binding of cGMP to the regulatory GAFa-GAFb domains of PDE6. The latter role of Pgamma has been attributed to its polycationic region. To elucidate the structural basis for the regulation of cGMP binding to the GAF domains of PDE6, a photoexcitable peptide probe corresponding to the polycationic region of Pgamma, Pgamma-21-45, was specifically cross-linked to rod PDE6alphabeta. The site of Pgamma-21-45 cross-linking was localized to Met138Gly139 within the PDE6alpha GAFa domain using mass spectrometric analysis. Chimeras between PDE5 and cone PDE6alpha', containing GAFa and/or GAFb domains of PDE6alpha' have been generated to probe a potential role of the GAFb domains in binding to Pgamma. Analysis of the inhibition of the PDE5/PDE6alpha' chimeras by Pgamma supported the role of PDE6 GAFa but not GAFb domains in the interaction with Pgamma. Our results suggest that a direct binding of the polycationic region of Pgamma to the GAFa domains of PDE6 may lead to a stabilization of the noncatalytic cGMP-binding sites.

Mutually exclusive expression of human red and green visual pigment-reporter transgenes occurs at high frequency in murine cone photoreceptors.

PubMed

Wang, Y; Smallwood, P M; Cowan, M; Blesh, D; Lawler, A; Nathans, J

1999-04-27

This study examines the mechanism of mutually exclusive expression of the human X-linked red and green visual pigment genes in their respective cone photoreceptors by asking whether this expression pattern can be produced in a mammal that normally carries only a single X-linked visual pigment gene. To address this question, we generated transgenic mice that carry a single copy of a minimal human X chromosome visual pigment gene array in which the red and green pigment gene transcription units were replaced, respectively, by alkaline phosphatase and beta-galactosidase reporters. As determined by histochemical staining, the reporters are expressed exclusively in cone photoreceptor cells. In 20 transgenic mice carrying any one of three independent transgene insertion events, an average of 63% of expressing cones have alkaline phosphatase activity, 10% have beta-galactosidase activity, and 27% have activity for both reporters. Thus, mutually exclusive expression of red and green pigment transgenes can be achieved in a large fraction of cones in a dichromat mammal, suggesting a facile evolutionary path for the development of trichromacy after visual pigment gene duplication. These observations are consistent with a model of visual pigment expression in which stochastic pairing occurs between a locus control region and either the red or the green pigment gene promotor.

Mutational studies in X-linked Charcot-Marie-Tooth disease (CMTX)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cherryson, A.K.; Yeung, L.; Kennerson, M.L.

1994-09-01

Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN), is a heterogeneous group of slowly progressive disorders of the peripheral nerve. X-linked CMT (CMTX) is characterized by slow motor nerve conduction velocities in affected males and the presence of mildly affected or normal carrier females with intermediate or normal nerve conduction velocities. CMTX, which has an incidence of 3.1 per 100,000 and accounts for approximately 10% of CMT cases, has been mapped to Xq13. One of the genes lying in this region, connexin 32, has been found to contain alterations in individuals affected with X-linked CMT. We havemore » identified our X-linked families from dominant type 1 CMT families using the clinical criteria given above. These families were screened for point mutations in connexin 32. We have identified three missense mutations, a G{r_arrow}A transition at amino acid 35 (valine to methionine), a C{r_arrow}G transition at amino acid 158 (proline to alanine) and a T{r_arrow}A transition at amino acid 182 (serine to threonine). Another family showed a 18 bp deletion, which removed the amino acid 111 to 116 inclusive (histidine, glycine, aspartic acid, proline, leucine, histidine).« less

Mapping the x-linked lymphoproliferative syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skare, J.C.; Milunsky, A.; Byron, K.S.

1987-04-01

The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predictmore » which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.« less

Long-term 12 year follow-up of X-linked congenital retinoschisis

PubMed Central

Kjellström, Sten; Vijayasarathy, Camasamudram; Ponjavic, Vesna; Sieving, Paul A.; Andréasson, Sten

2010-01-01

Purpose To investigate the retinal structure and function during the progression of X-linked retinoschisis (XLRS) from childhood to adulthood. Methods Ten patients clinically diagnosed with XLRS were investigated at 6–15 years of age (mean age 9 years) with a follow-up 8 to 14 years later (mean 12 years). The patients underwent regular ophthalmic examination as well as testing of best corrected visual acuity (BCVA), visual field (VF) and assessment of full-field electroretinography (ERG) during their first visit. During the follow-up, the same clinical protocols were repeated. In addition, macular structure and function was examined with multifocal electroretinography (mfERG) and optical coherence tomography (OCT). The patients were 18–25 years of age (mean age 21 years) at the follow-up examination. All exons and exon-intron boundaries of RS1-gene were sequenced for gene mutations in 9 out of the 10 patients. Results Best corrected VA and VF were stable during this follow-up period. No significant progression in cone or rod function could be measured by full-field ERG. Multifocal electroretinography and OCT demonstrated a wide heterogeneity of macular changes in retinal structure and function at the time of follow-up visit. Three different mutations were detected in these nine patients, including a known nonsense mutation in exon 3, a novel insertion in exon 5 and an intronic mutation at 5' splice site of intron 3. Conclusions Clinical follow-up (mean 12 years) of ten young XLRS patients (mean age of 9 years) with a typical congenital retinoschisis phenotype revealed no significant decline in retinal function during this time period. MfERG and OCT demonstrated a wide variety of macular changes including structure and dysfunction. The XLRS disease was relatively stable during this period of observation and would afford opportunity for therapy studies to judge benefit against baseline and against the fellow eye. PMID:20569020

The evolution of rod photoreceptors

PubMed Central

Morshedian, Ala

2017-01-01

Photoreceptors in animals are generally of two kinds: the ciliary or c-type and the rhabdomeric or r-type. Although ciliary photoreceptors are found in many phyla, vertebrates seem to be unique in having two distinct kinds which together span the entire range of vision, from single photons to bright light. We ask why the principal photoreceptors of vertebrates are ciliary and not rhabdomeric, and how rods evolved from less sensitive cone-like photoreceptors to produce our duplex retina. We suggest that the principal advantage of vertebrate ciliary receptors is that they use less ATP than rhabdomeric photoreceptors. This difference may have provided sufficient selection pressure for the development of a completely ciliary eye. Although many of the details of rod evolution are still uncertain, present evidence indicates that (i) rods evolved very early before the split between the jawed and jawless vertebrates, (ii) outer-segment discs make no contribution to rod sensitivity but may have evolved to increase the efficiency of protein renewal, and (iii) evolution of the rod was incremental and multifaceted, produced by the formation of several novel protein isoforms and by changes in protein expression, with no one alteration having more than a few-fold effect on transduction activation or inactivation. This article is part of the themed issue ‘Vision in dim light’. PMID:28193819

The evolution of rod photoreceptors.

PubMed

Morshedian, Ala; Fain, Gordon L

2017-04-05

Photoreceptors in animals are generally of two kinds: the ciliary or c-type and the rhabdomeric or r-type. Although ciliary photoreceptors are found in many phyla, vertebrates seem to be unique in having two distinct kinds which together span the entire range of vision, from single photons to bright light. We ask why the principal photoreceptors of vertebrates are ciliary and not rhabdomeric, and how rods evolved from less sensitive cone-like photoreceptors to produce our duplex retina. We suggest that the principal advantage of vertebrate ciliary receptors is that they use less ATP than rhabdomeric photoreceptors. This difference may have provided sufficient selection pressure for the development of a completely ciliary eye. Although many of the details of rod evolution are still uncertain, present evidence indicates that (i) rods evolved very early before the split between the jawed and jawless vertebrates, (ii) outer-segment discs make no contribution to rod sensitivity but may have evolved to increase the efficiency of protein renewal, and (iii) evolution of the rod was incremental and multifaceted, produced by the formation of several novel protein isoforms and by changes in protein expression, with no one alteration having more than a few-fold effect on transduction activation or inactivation.This article is part of the themed issue 'Vision in dim light'. © 2017 The Author(s).

Ontogenic retinal changes in three ecologically distinct elopomorph fishes (Elopomorpha:Teleostei) correlate with light environment and behavior.

PubMed

Taylor, Scott M; Loew, Ellis R; Grace, Michael S

2015-01-01

Unlike the mammalian retina, the teleost fish retina undergoes persistent neurogenesis from intrinsic stem cells. In marine teleosts, most cone photoreceptor genesis occurs early in the embryonic and larval stages, and rods are added primarily during and after metamorphosis. This study demonstrates a developmental paradigm in elopomorph fishes in which retinas are rod-dominated in larvae, but undergo periods of later cone genesis. Retinal characteristics were compared at different developmental stages among three ecologically distinct elopomorph fishes-ladyfish (Elops saurus), bonefish (Albula vulpes), and speckled worm eel (Myrophis punctatus). The objectives were to improve our understanding of (1) the developmental strategy in the elopomorph retina, (2) the functional architecture of the retina as it relates to ecology, and (3) how the light environment influences photoreceptor genesis. Photoreceptor morphologies, distributions, and spectral absorption were studied at larval, juvenile, and adult stages. Premetamorphic retinas in all three species are rod-dominated, but the retinas of these species undergo dramatic change over the course of development, resulting in juvenile and adult retinal characteristics that correlate closely with ecology. Adult E. saurus has high rod densities, grouped photoreceptors, a reflective tapetum, and longer-wavelength photopigments, supporting vision in turbid, low-light conditions. Adult A. vulpes has high cone densities, low rod densities, and shorter-wavelength photopigments, supporting diurnal vision in shallow, clear water. M. punctatus loses cones during metamorphosis, develops new cones after settlement, and maintains high rod but low cone densities, supporting primarily nocturnal vision. M. punctatus secondary cone genesis occurs rapidly throughout the retina, suggesting a novel mechanism of vertebrate photoreceptor genesis. Finally, in postsettlement M. punctatus, the continuous presence or absence of visible light

X-ray Crystal Truncation Rod Studies of Surface Oxidation and Reduction on Pt(111)

DOE PAGES

Liu, Yihua; Barbour, Andi; Komanicky, Vladimir; ...

2016-02-26

Here, we present X-ray crystal truncation rods measurements of Pt(111) surface under electrochemical conditions. Analyses of crystal truncation rods reveal that surface oxide formation buckles the top surface layer of platinum to two different heights at the potential (0.95 V vs RHE) below the so-called place-exchange potential. While the anti-Bragg intensity, sensitive to the top surface layer, drops in response to the anodic charge transfers, its responses to the cathodic charge transfers are significantly delayed. Implications to the surface oxidation and reduction behaviors are discussed.

Emotionality of Colors: An Implicit Link between Red and Dominance.

PubMed

Mentzel, Stijn V; Schücker, Linda; Hagemann, Norbert; Strauss, Bernd

2017-01-01

The color red has been shown to alter emotions, physiology, psychology, and behavior. Research has suggested that these alterations could possibly be due to a link between red and perceived dominance. In this study we examined if the color red is implicitly associated to the concept of dominance. In addition, we similarly hypothesized that blue is implicitly linked to rest. A modified Stroop word evaluation task was used in which 30 participants (23.07 ± 4.42 years) were asked to classify words shown in either red, blue, or gray (control condition), as being either dominant- or rest-related. The responses were recorded and analyzed for latency time and accuracy. The results revealed a significant word type × color interaction effect for both latency times, F (2,56) = 5.09, p = 0.009, [Formula: see text] = 0.15, and accuracy, F (1.614,45.193) = 8.57, p = 0.001, [Formula: see text] = 0.23. On average participants showed significantly shorter latency times and made less errors when categorizing dominance words shown in red, compared to blue and gray. The measured effects show strong evidence for an implicit red-dominance association and a partial red-rest disassociation. It is discussed that this association can possibly affect emotionality, with the presentation of red eliciting a dominant emotional and behavioral response.

Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants

PubMed Central

Jacobson, Samuel G.; Cideciyan, Artur V.; Peshenko, Igor V.; Sumaroka, Alexander; Olshevskaya, Elena V.; Cao, Lihui; Schwartz, Sharon B.; Roman, Alejandro J.; Olivares, Melani B.; Sadigh, Sam; Yau, King-Wai; Heon, Elise; Stone, Edwin M.; Dizhoor, Alexander M.

2013-01-01

The GUCY2D gene encodes retinal membrane guanylyl cyclase (RetGC1), a key component of the phototransduction machinery in photoreceptors. Mutations in GUCY2D cause Leber congenital amaurosis type 1 (LCA1), an autosomal recessive human retinal blinding disease. The effects of RetGC1 deficiency on human rod and cone photoreceptor structure and function are currently unknown. To move LCA1 closer to clinical trials, we characterized a cohort of patients (ages 6 months—37 years) with GUCY2D mutations. In vivo analyses of retinal architecture indicated intact rod photoreceptors in all patients but abnormalities in foveal cones. By functional phenotype, there were patients with and those without detectable cone vision. Rod vision could be retained and did not correlate with the extent of cone vision or age. In patients without cone vision, rod vision functioned unsaturated under bright ambient illumination. In vitro analyses of the mutant alleles showed that in addition to the major truncation of the essential catalytic domain in RetGC1, some missense mutations in LCA1 patients result in a severe loss of function by inactivating its catalytic activity and/or ability to interact with the activator proteins, GCAPs. The differences in rod sensitivities among patients were not explained by the biochemical properties of the mutants. However, the RetGC1 mutant alleles with remaining biochemical activity in vitro were associated with retained cone vision in vivo. We postulate a relationship between the level of RetGC1 activity and the degree of cone vision abnormality, and argue for cone function being the efficacy outcome in clinical trials of gene augmentation therapy in LCA1. PMID:23035049

X-ray microtomography study of the compaction process of rods under tapping.

PubMed

Fu, Yang; Xi, Yan; Cao, Yixin; Wang, Yujie

2012-05-01

We present an x-ray microtomography study of the compaction process of cylindrical rods under tapping. The process is monitored by measuring the evolution of the orientational order parameter, local, and overall packing densities as a function of the tapping number for different tapping intensities. The slow relaxation dynamics of the orientational order parameter can be well fitted with a stretched-exponential law with stretching exponents ranging from 0.9 to 1.6. The corresponding relaxation time versus tapping intensity follows an Arrhenius behavior which is reminiscent of the slow dynamics in thermal glassy systems. We also investigated the boundary effect on the ordering process and found that boundary rods order faster than interior ones. In searching for the underlying mechanism of the slow dynamics, we estimated the initial random velocities of the rods under tapping and found that the ordering process is compatible with a diffusion mechanism. The average coordination number as a function of the tapping number at different tapping intensities has also been measured, which spans a range from 6 to 8.

The retina visual cycle is driven by cis retinol oxidation in the outer segments of cones

PubMed Central

Sato, Shinya; Frederiksen, Rikard; Cornwall, M. Carter; Kefalov, Vladimir J.

2017-01-01

Vertebrate rod and cone photoreceptors require continuous supply of chromophore for regenerating their visual pigments after photoactivation. Cones, which mediate our daytime vision, demand a particularly rapid supply of 11-cis retinal chromophore in order to maintain their function in bright light. An important contribution to this process is thought to be the chromophore precursor 11-cis retinol, which is supplied to cones from Müller cells in the retina and subsequently oxidized to 11-cis retinal as part of the retina visual cycle. However, the molecular identity of the cis retinol oxidase in cones remains unclear. Here, as a first step in characterizing this enzymatic reaction, we sought to determine the subcellular localization of this activity in salamander red cones. We found that the onset of dark adaptation of isolated salamander red cones was substantially faster when exposing directly their outer vs. their inner segment to 9-cis retinol, an analogue of 11-cis retinol. In contrast, this difference was not observed when treating the outer vs. inner segment with 9-cis retinal, a chromophore analogue which can directly support pigment regeneration. These results suggest, surprisingly, that the cis-retinol oxidation occurs in the outer segments of cone photoreceptors. Confirming this notion, pigment regeneration with exogenously added 9-cis retinol was directly observed in the truncated outer segments of cones, but not in rods. We conclude that the enzymatic machinery required for the oxidation of recycled cis retinol as part of the retina visual cycle is present in the outer segments of cones. PMID:28359344

Novel Animal Model of Crumbs-Dependent Progressive Retinal Degeneration That Targets Specific Cone Subtypes.

PubMed

Fu, Jinling; Nagashima, Mikiko; Guo, Chuanyu; Raymond, Pamela A; Wei, Xiangyun

2018-01-01

Human Crb1 is implicated in some forms of retinal degeneration, suggesting a role in photoreceptor maintenance. Multiple Crumbs (Crb) polarity genes are expressed in vertebrate retina, although their functional roles are not well understood. To gain further insight into Crb and photoreceptor maintenance, we compared retinal cell densities between wild-type and Tg(RH2-2:Crb2b-sfEX/RH2-2:GFP)pt108b transgenic zebrafish, in which the extracellular domain of Crb2b-short form (Crb2b-sfEX) is expressed in the retina as a secreted protein, which disrupts the planar organization of RGB cones (red, green, and blue) by interfering with Crb2a/2b-based cone-cone adhesion. We used standard morphometric techniques to assess age-related changes in retinal cell densities in adult zebrafish (3 to 27 months old), and to assess effects of the Crb2b-sfEX transgene on retinal structure and photoreceptor densities. Linear cell densities were measured in all retinal layers in radial sections with JB4-Feulgen histology. Planar (surface) densities of cones were determined in retinal flat-mounts. Cell counts from wild-type and pt108b transgenic fish were compared with both a "photoreceptor maintenance index" and statistical analysis of cell counts. Age-related changes in retinal cell linear densities and cone photoreceptor planar densities in wild-type adult zebrafish provided a baseline for analysis. Expression of Crb2b-sfEX caused progressive and selective degeneration of RGB cones, but had no effect on ultraviolet-sensitive (UV) cones, and increased numbers of rod photoreceptors. These differential responses of RGB cones, UV cones, and rods to sustained exposure to Crb2b-sfEX suggest that Crb-based photoreceptor maintenance mechanisms are highly selective.

Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina

PubMed Central

Merriman, Dana K.; Sajdak, Benjamin S.; Li, Wei; Jones, Bryan W.

2016-01-01

With a photoreceptor mosaic containing ~85% cones, the ground squirrel is one of the richest known mammalian sources of these important retinal cells. It also has a visual ecology much like the human’s. While the ground squirrel retina is understandably prominent in the cone biochemistry, physiology, and circuitry literature, far less is known about the remodeling potential of its retinal pigment epithelium, neurons, macroglia, or microglia. This review aims to summarize the data from ground squirrel retina to this point in time, and to relate them to data from other brain areas where appropriate. We begin with a survey of the ground squirrel visual system, making comparisons with traditional rodent models and with human. Because this animal’s status as a hibernator often goes unnoticed in the vision literature, we then present a brief primer on hibernation biology. Next we review what is known about ground squirrel retinal remodeling concurrent with deep torpor and with rapid recovery upon re-warming. Notable here is rapidly-reversible, temperature-dependent structural plasticity of cone ribbon synapses, as well as pre- and post-synaptic plasticity throughout diverse brain regions. It is not yet clear if retinal cell types other than cones engage in torpor-associated synaptic remodeling. We end with the small but intriguing literature on the ground squirrel retina’s remodeling responses to insult by retinal detachment. Notable for widespread loss of (cone) photoreceptors, there is surprisingly little remodeling of the RPE or Müller cells. Microglial activation appears minimal, and remodeling of surviving second- and third-order neurons seems absent, but both require further study. In contrast, traumatic brain injury in the ground squirrel elicits typical macroglial and microglial responses. Overall, the data to date strongly suggest a heretofore unrecognized, natural checkpoint between retinal deafferentiation and RPE and Müller cell remodeling events. As

Genetics Home Reference: X-linked severe combined immunodeficiency

MedlinePlus

... Facebook Twitter Home Health Conditions X-linked SCID X-linked severe combined immunodeficiency Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked severe combined immunodeficiency (SCID) is an inherited ...

Genetics Home Reference: X-linked adrenal hypoplasia congenita

MedlinePlus

... Home Health Conditions X-linked adrenal hypoplasia congenita X-linked adrenal hypoplasia congenita Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked adrenal hypoplasia congenita is a disorder that ...

Genetics Home Reference: X-linked chondrodysplasia punctata 1

MedlinePlus

... Home Health Conditions X-linked chondrodysplasia punctata 1 X-linked chondrodysplasia punctata 1 Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked chondrodysplasia punctata 1 is a disorder of ...

Optimization over Multi-order Cones

DTIC Science & Technology

2011-02-01

Department of Mathematics Technical Report 2011-1 Optimization over multi-order cones Baha ’ M. Alzalg and K. A. Ariyawansa February 2011 Postal...Prescribed by ANSI Std Z39-18 Optimization over multi-order cones Baha M. Alzalg∗ and K. A. Ariyawansa† Abstract In this paper we propose multi-order cone...that x ∈ Qnp , and x 〈n〉 〈p〉 y to mean that x− y 〈n〉 〈p〉 0. Given 1 ≤ pi ≤ ∞ for i = 1, 2, · · · , r. Let Q 〈n1,n2,··· ,nr〉 〈p1,p2,··· ,pr〉 := Qn1p1

Dark-Adapted Chromatic Perimetry for Measuring Rod Visual Fields in Patients with Retinitis Pigmentosa

PubMed Central

Bennett, Lea D.; Klein, Martin; Locke, Kirsten G.; Kiser, Kelly; Birch, David G.

2017-01-01

Purpose Although rod photoreceptors are initially affected in retinitis pigmentosa (RP), the full-field of rod vision is not routinely characterized due to the unavailability of commercial devices detecting rod sensitivity. The purpose of this study was to quantify rod-mediated vision in the peripheral field from patients with RP using a new commercially available perimeter. Methods Participants had one eye dilated and dark-adapted for 45 minutes. A dark-adapted chromatic (DAC) perimeter tested 80 loci 144° horizontally and 72° vertically with cyan stimuli. The number of rod-mediated loci (RML) were analyzed based on normal cone sensitivity (method 1) and associated with full-field electroretinography (ERG) responses by Pearson's r correlation and linear regression. In a second cohort of patients with RP, RML were identified by two-color perimetry (cyan and red; method 2). The two methods for ascribing rod function were compared by Bland-Altman analysis. Results Method 1 RML were correlated with responses to the 0.01 cd.s/m2 flash (P < 0.001), while total sensitivity to the cyan stimulus showed correlation with responses to the 3.0 cd.s/m2 flash (P < 0.0001). Method 2 detected a mean of 10 additional RML compared to method 1. Conclusions Scotopic fields measured with the DAC detected rod sensitivity across the full visual field, even in some patients who had nondetectable rod ERGs. Two-color perimetry is warranted when sensitivity to the cyan stimulus is reduced to ≤20 dB to get a true estimation of rod function. Translational Relevance Many genetic forms of retinitis pigmentosa (RP) are caused by mutations in rod-specific genes. However, treatment trials for patients with RP have relied primarily on photopic (cone-mediated) tests as outcome measures because there are a limited number of available testing methods designed to evaluate rod function. Thus, efficient methods for quantifying rod-mediated vision are needed for the rapidly increasing numbers of

Purification and characterization of bovine cone arrestin (cArr).

PubMed

Maeda, T; Ohguro, H; Sohma, H; Kuroki, Y; Wada, H; Okisaka, S; Murakami, A

2000-03-31

To elucidate the quenching mechanism of phototransduction in vertebrate cone photoreceptors, a cDNA clone encoding cone specific arrestin (cArr) was isolated from a bovine retinal cDNA library using a human cArr cDNA probe. Affinity-purified anti-peptide antibody specific to cArr was prepared. Immunohistochemical staining displayed specific labeling of cArr in cone photoreceptors and immunoblotting identified a 46 kDa protein band. We purified cArr from bovine retinas by sequential column chromatography using DEAE-cellulose, gel filtration and mono Q columns. Binding studies revealed no binding of cArr to rhodopsin regardless of whether it was bleached and/or phosphorylated. cArr also failed to bind to heparin-Sepharose under conditions which rod arrestin (rArr) bound to the column. The present data suggest that cArr may play a role in the quenching of phototransduction in cone photoreceptors and that its activity therein is different to that of rArr.

Canine RD3 mutation establishes rod cone dysplasia type 2 (rcd2) as ortholog of human and murine rd3

PubMed Central

Kukekova, Anna V.; Goldstein, Orly; Johnson, Jennifer L.; Richardson, Malcolm A.; Pearce-Kelling, Susan E.; Swaroop, Anand; Friedman, James S.; Aguirre, Gustavo D.; Acland, Gregory M.

2009-01-01

Rod cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed, and to fine map rcd2 to a 230 kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2, and is predicted to alter the last 61 codons of the normal open reading frame and further extend the ORF. Thus combined meiotic linkage and LD mapping within a single canine breed can yield critical reduction of the disease interval when appropriate advantage is taken of within breed population structure. This should permit a similar approach to tackle other hereditary traits that segregate in single closed populations. PMID:19130129

Light adaptation alters the source of inhibition to the mouse retinal OFF pathway

PubMed Central

Mazade, Reece E.

2013-01-01

Sensory systems must avoid saturation to encode a wide range of stimulus intensities. One way the retina accomplishes this is by using both dim-light-sensing rod and bright-light-sensing cone photoreceptor circuits. OFF cone bipolar cells are a key point in this process, as they receive both excitatory input from cones and inhibitory input from AII amacrine cells via the rod pathway. However, in addition to AII amacrine cell input, other inhibitory inputs from cone pathways also modulate OFF cone bipolar cell light signals. It is unknown how these inhibitory inputs to OFF cone bipolar cells change when switching between rod and cone pathways or whether all OFF cone bipolar cells receive rod pathway input. We found that one group of OFF cone bipolar cells (types 1, 2, and 4) receive rod-mediated inhibitory inputs that likely come from the rod-AII amacrine cell pathway, while another group of OFF cone bipolar cells (type 3) do not. In both cases, dark-adapted rod-dominant light responses showed a significant contribution of glycinergic inhibition, which decreased with light adaptation and was, surprisingly, compensated by an increase in GABAergic inhibition. As GABAergic input has distinct timing and spatial spread from glycinergic input, a shift from glycinergic to GABAergic inhibition could significantly alter OFF cone bipolar cell signaling to downstream OFF ganglion cells. Larger GABAergic input could reflect an adjustment of OFF bipolar cell spatial inhibition, which may be one mechanism that contributes to retinal spatial sensitivity in the light. PMID:23926034

Loss and gain of cone types in vertebrate ciliary photoreceptor evolution.

PubMed

Musser, Jacob M; Arendt, Detlev

2017-11-01

Ciliary photoreceptors are a diverse cell type family that comprises the rods and cones of the retina and other related cell types such as pineal photoreceptors. Ciliary photoreceptor evolution has been dynamic during vertebrate evolution with numerous gains and losses of opsin and phototransduction genes, and changes in their expression. For example, early mammals lost all but two cone opsins, indicating loss of cone receptor types in response to nocturnal lifestyle. Our review focuses on the comparison of specifying transcription factors and cell type-specific transcriptome data in vertebrate retinae to build and test hypotheses on ciliary photoreceptor evolution. Regarding cones, recent data reveal that a combination of factors specific for long-wavelength sensitive opsin (Lws)- cones in non-mammalian vertebrates (Thrb and Rxrg) is found across all differentiating cone photoreceptors in mice. This suggests that mammalian ancestors lost all but one ancestral cone type, the Lws-cone. We test this hypothesis by a correlation analysis of cone transcriptomes in mouse and chick, and find that, indeed, transcriptomes of all mouse cones are most highly correlated to avian Lws-cones. These findings underscore the importance of specifying transcription factors in tracking cell type evolution, and shed new light on the mechanisms of cell type loss and gain in retina evolution. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Sodium-dependent calcium extrusion and sensitivity regulation in retinal cones of the salamander.

PubMed Central

Nakatani, K; Yau, K W

1989-01-01

1. Membrane current was recorded from an isolated, dark-adapted salamander cone by sucking its inner segment into a tight-fitting glass pipette containing Ringer solution. The outer segment of the cell was exposed to a bath solution that could be changed rapidly. 2. After removing Na+ from the bath Ringer solution for a short period of time in darkness (the 'loading period'), a transient inward current was observed upon restoring it in bright light. A similar but longer-lasting current was observed when Na+ was restored in the light after a large Ca2+ influx was induced through the light-sensitive conductance in darkness. 3. The above transient current was not observed if Li+ or guanidinium was substituted for Na+ in the light, or if Ba2+ was substituted for Ca2+ during the dark loading period. However, a current was observed if Sr2+ was the substituting ion for Ca2+ during loading. These observations suggested that the current was associated with an electrogenic Na+-dependent Ca2+ efflux at the cone outer segment. 4. The saturated amplitude of the exchange current was 12-25 pA with a mean around 16 pA. This is very comparable to that measured in the outer segment of a salamander rod under similar conditions. 5. By comparing a known Ca2+ load in a cone outer segment to the subsequent charge transfer through the exchange, we estimated that the stoichiometry of the exchange was near 3Na+:1Ca2+. 6. With a small Ca2+ load, or in the presence of Cs+ around the inner segment, the final temporal decline of the Na+-Ca2+ exchange current was roughly exponential, with a mean time constant of about 100 ms. This decline is about four times faster than that measured in rods. We interpret the shorter time constant in cones to reflect a faster rate of decline of intracellular free Ca2+ in their outer segments resulting from the exchange activity. 7. In the absence of external Na+, and hence any Na+-dependent Ca2+ efflux, the absolute sensitivity of a cone to a dim flash was

Genetic localization and phenotypic expression of X-linked cataract (Xcat) in Mus musculus.

PubMed

Favor, J; Pretsch, W

1990-01-01

Linkage data relative to the markers tabby and glucose-6-phosphate dehydrogenase are presented to locate X-linked cataract (Xcat) in the distal portion of the mouse X-chromosome between jimpy and hypophosphatemia. The human X-linked cataract-dental syndrome, Nance-Horan Syndrome, also maps closely to human hypophosphatemia and would suggest homology between mouse Xcat and human Nance-Horan Syndrome genes. In hemizygous males and homozygous females penetrance is complete with only slight variation in the degree of expression. Phenotypic expression in Xcat heterozygous females ranges from totally clear to totally opaque lenses. The phenotypic expression between the two lenses of a heterozygous individual could also vary between totally clear and totally opaque lenses. However, a correlation in the degree of expression between the eyes of an individual was observed. A variegated pattern of lens opacity was evident in female heterozygotes. Based on these observations, the site of gene action for the Xcat locus is suggested to be endogenous to the lens cells and the precursor cell population of the lens is concluded to be small. The identification of an X-linked cataract locus is an important contribution to the estimate of the number of mutable loci resulting in cataract, an estimate required so that dominant cataract mutagenesis results may be expressed on a per locus basis. The Xcat mutation may be a useful marker for a distal region of the mouse X-chromosome which is relatively sparsely marked and the X-linked cataract mutation may be employed in gene expression and lens development studies.

Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia

USDA-ARS?s Scientific Manuscript database

Focal dermal hypoplasia is an X-linked dominant disorder characterized by patchy hypoplastic skin and digital, ocular, and dental malformations. We used array comparative genomic hybridization to identify a 219-kb deletion in Xp11.23 in two affected females. We sequenced genes in this region and fou...

Optimized x-ray source scanning trajectories for iterative reconstruction in high cone-angle tomography

NASA Astrophysics Data System (ADS)

Kingston, Andrew M.; Myers, Glenn R.; Latham, Shane J.; Li, Heyang; Veldkamp, Jan P.; Sheppard, Adrian P.

2016-10-01

With the GPU computing becoming main-stream, iterative tomographic reconstruction (IR) is becoming a com- putationally viable alternative to traditional single-shot analytical methods such as filtered back-projection. IR liberates one from the continuous X-ray source trajectories required for analytical reconstruction. We present a family of novel X-ray source trajectories for large-angle CBCT. These discrete (sparsely sampled) trajectories optimally fill the space of possible source locations by maximising the degree of mutually independent information. They satisfy a discrete equivalent of Tuy's sufficiency condition and allow high cone-angle (high-flux) tomog- raphy. The highly isotropic nature of the trajectory has several advantages: (1) The average source distance is approximately constant throughout the reconstruction volume, thus avoiding the differential-magnification artefacts that plague high cone-angle helical computed tomography; (2) Reduced streaking artifacts due to e.g. X-ray beam-hardening; (3) Misalignment and component motion manifests as blur in the tomogram rather than double-edges, which is easier to automatically correct; (4) An approximately shift-invariant point-spread-function which enables filtering as a pre-conditioner to speed IR convergence. We describe these space-filling trajectories and demonstrate their above-mentioned properties compared with a traditional helical trajectories.

Characterization of Scattered X-Ray Photons in Dental Cone-Beam Computed Tomography.

PubMed

Yang, Ching-Ching

2016-01-01

Scatter is a very important artifact causing factor in dental cone-beam CT (CBCT), which has a major influence on the detectability of details within images. This work aimed to improve the image quality of dental CBCT through scatter correction. Scatter was estimated in the projection domain from the low frequency component of the difference between the raw CBCT projection and the projection obtained by extrapolating the model fitted to the raw projections acquired with 2 different sizes of axial field-of-view (FOV). The function for curve fitting was optimized by using Monte Carlo simulation. To validate the proposed method, an anthropomorphic phantom and a water-filled cylindrical phantom with rod inserts simulating different tissue materials were scanned using 120 kVp, 5 mA and 9-second scanning time covering an axial FOV of 4 cm and 13 cm. The detectability of the CT image was evaluated by calculating the contrast-to-noise ratio (CNR). Beam hardening and cupping artifacts were observed in CBCT images without scatter correction, especially in those acquired with 13 cm FOV. These artifacts were reduced in CBCT images corrected by the proposed method, demonstrating its efficacy on scatter correction. After scatter correction, the image quality of CBCT was improved in terms of target detectability which was quantified as the CNR for rod inserts in the cylindrical phantom. Hopefully the calculations performed in this work can provide a route to reach a high level of diagnostic image quality for CBCT imaging used in oral and maxillofacial structures whilst ensuring patient dose as low as reasonably achievable, which may ultimately make CBCT scan a reliable and safe tool in clinical practice.

Feasibility of using cone penetrometer truck (CPT) to install time domain reflectometry (TDR) and fiber optic slope failure detectors in pavement structures.

DOT National Transportation Integrated Search

2011-02-01

A new method of cable installation using a heavy-duty Cone Penetration Test : (CPT) truck was developed and practiced successfully in this study. The coaxial and fiber : optic cables were pushed along with the cone rods by the hydraulic system integr...

Semi-automated identification of cones in the human retina using circle Hough transform

PubMed Central

Bukowska, Danuta M.; Chew, Avenell L.; Huynh, Emily; Kashani, Irwin; Wan, Sue Ling; Wan, Pak Ming; Chen, Fred K

2015-01-01

A large number of human retinal diseases are characterized by a progressive loss of cones, the photoreceptors critical for visual acuity and color perception. Adaptive Optics (AO) imaging presents a potential method to study these cells in vivo. However, AO imaging in ophthalmology is a relatively new phenomenon and quantitative analysis of these images remains difficult and tedious using manual methods. This paper illustrates a novel semi-automated quantitative technique enabling registration of AO images to macular landmarks, cone counting and its radius quantification at specified distances from the foveal center. The new cone counting approach employs the circle Hough transform (cHT) and is compared to automated counting methods, as well as arbitrated manual cone identification. We explore the impact of varying the circle detection parameter on the validity of cHT cone counting and discuss the potential role of using this algorithm in detecting both cones and rods separately. PMID:26713186

Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration.

PubMed

Briggs, C E; Rucinski, D; Rosenfeld, P J; Hirose, T; Berson, E L; Dryja, T P

2001-09-01

To determine the spectrum of ABCR mutations associated with Stargardt macular degeneration and cone-rod degeneration (CRD). One hundred eighteen unrelated patients with recessive Stargardt macular degeneration and eight with recessive CRD were screened for mutations in ABCR (ABCA4) by single-strand conformation polymorphism analysis. Variants were characterized by direct genomic sequencing. Segregation analysis was performed on the families of 20 patients in whom at least two or more likely pathogenic sequence changes were identified. The authors found 77 sequence changes likely to be pathogenic: 21 null mutations (15 novel), 55 missense changes (26 novel), and one deletion of a consensus glycosylation site (also novel). Fifty-two patients with Stargardt macular degeneration (44% of those screened) and five with CRD each had two of these sequence changes or were homozygous for one of them. Segregation analyses in the families of 19 of these patients were informative and revealed that the index cases and all available affected siblings were compound heterozygotes or homozygotes. The authors found one instance of an apparently de novo mutation, Ile824Thr, in a patient. Thirty-seven (31%) of the 118 patients with Stargardt disease and one with CRD had only one likely pathogenic sequence change. Twenty-nine patients with Stargardt disease (25%) and two with CRD had no identified sequence changes. This report of 42 novel mutations brings the growing number of identified likely pathogenic sequence changes in ABCR to approximately 250.

Nanofocus x-ray diffraction and cathodoluminescence investigations into individual core-shell (In,Ga)N/GaN rod light-emitting diodes.

PubMed

Krause, Thilo; Hanke, Michael; Cheng, Zongzhe; Niehle, Michael; Trampert, Achim; Rosenthal, Martin; Burghammer, Manfred; Ledig, Johannes; Hartmann, Jana; Zhou, Hao; Wehmann, Hergo-Heinrich; Waag, Andreas

2016-08-12

Employing nanofocus x-ray diffraction, we investigate the local strain field induced by a five-fold (In,Ga)N multi-quantum well embedded into a GaN micro-rod in core-shell geometry. Due to an x-ray beam width of only 150 nm in diameter, we are able to distinguish between individual m-facets and to detect a significant in-plane strain gradient along the rod height. This gradient translates to a red-shift in the emitted wavelength revealed by spatially resolved cathodoluminescence measurements. We interpret the result in terms of numerically derived in-plane strain using the finite element method and subsequent kinematic scattering simulations which show that the driving parameter for this effect is an increasing indium content towards the rod tip.

Nanofocus x-ray diffraction and cathodoluminescence investigations into individual core-shell (In,Ga)N/GaN rod light-emitting diodes

NASA Astrophysics Data System (ADS)

Krause, Thilo; Hanke, Michael; Cheng, Zongzhe; Niehle, Michael; Trampert, Achim; Rosenthal, Martin; Burghammer, Manfred; Ledig, Johannes; Hartmann, Jana; Zhou, Hao; Wehmann, Hergo-Heinrich; Waag, Andreas

2016-08-01

Employing nanofocus x-ray diffraction, we investigate the local strain field induced by a five-fold (In,Ga)N multi-quantum well embedded into a GaN micro-rod in core-shell geometry. Due to an x-ray beam width of only 150 nm in diameter, we are able to distinguish between individual m-facets and to detect a significant in-plane strain gradient along the rod height. This gradient translates to a red-shift in the emitted wavelength revealed by spatially resolved cathodoluminescence measurements. We interpret the result in terms of numerically derived in-plane strain using the finite element method and subsequent kinematic scattering simulations which show that the driving parameter for this effect is an increasing indium content towards the rod tip.

Platelet-Derived Growth Factor-BB Lessens Light-Induced Rod Photoreceptor Damage in Mice.

PubMed

Takahashi, Kei; Shimazawa, Masamitsu; Izawa, Hiroshi; Inoue, Yuki; Kuse, Yoshiki; Hara, Hideaki

2017-12-01

Platelet-derived growth factor (PDGF)-BB is known to have neuroprotective effects against various neurodegenerative disorders. The purpose of this study was to determine whether PDGF-BB can be neuroprotective against light-induced photoreceptor damage in mice. Mice were exposed to 8000-lux luminance for 3 hours to induce phototoxicity. Two hours before light exposure, the experimental mice were injected with PDGF-BB intravitreally, and the control mice were injected with phosphate-buffered saline. The light-exposed PDGF-BB-injected mice and saline-injected mice were evaluated electroretinographically and histologically. The site and expression levels of PDGFR-β and PDGF-BB were determined by immunostaining and Western blotting, respectively. The effect of PDGF-BB on light-induced cone and rod photoreceptor damage was also evaluated in vitro in 661W cells, a murine cone photoreceptor cell line, and in primary retinal cell cultures. An intravitreal injection of PDGF-BB significantly reduced the decrease in the amplitudes of the electroretinograms (ERGs) and the thinning of the outer nuclear layer (ONL) induced by the light exposure. It also reduced the number of TUNEL-positive cells in the ONL. PDGFR-β was expressed in the rod outer segments (OSs) but not the cone OSs. The levels of PDGF-BB and PDGFR-β were decreased after light irradiation. In addition, PDGF-BB had protective effects against light-induced damage to cells of rod photoreceptors but had no effect on the 661W cells in vitro. These findings indicate that PDGF-BB reduces the degree of light-induced retinal damage by activating PDGFR-β in rod photoreceptors. These findings suggest that PDGF-BB could play a role in the prevention of degeneration in eyes susceptible to phototoxicity.

Linkage Disequilibrium Mapping in Domestic Dog Breeds Narrows the Progressive Rod-Cone Degeneration (prcd) Interval and Identifies Ancestral Disease Transmitting Chromosome

PubMed Central

Goldstein, Orly; Zangerl, Barbara; Pearce-Kelling, Sue; Sidjanin, Duska J.; Kijas, James W.; Felix, Jeanette; Acland, Gregory M; Aguirre, Gustavo D.

2014-01-01

Canine progressive rod-cone degeneration (prcd) is a retinal disease previously mapped to a broad, gene-rich centromeric region of canine chromosome 9. As allelic disorders are present in multiple breeds, we used linkage disequilibrium (LD) to narrow the ∼6.4 Mb interval candidate region. Multiple dog breeds, each representing genetically isolated populations, were typed for SNPs and other polymorphisms identified from BACs. The candidate region was initially localized to a 1.5 Mb zero recombination interval between growth factor receptor-bound protein 2 (GRB2) and SEC14-like 1 (SEC14L). A fine-scale haplotype of the region was developed which reduced the LD interval to 106 Kb, and identified a conserved haplotype of 98 polymorphisms present in all prcd-affected chromosomes from 14 different dog breeds. The findings strongly suggest that a common ancestor transmitted the prcd disease allele to many of the modern dog breeds, and demonstrate the power of LD approach in the canine model. PMID:16859891

Pyoderma gangrenosum-like ulcer in a patient with X-linked agammaglobulinemia: identification of Helicobacter bilis by mass spectrometry analysis.

PubMed

Murray, Patrick R; Jain, Ashish; Uzel, Gulbu; Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B; Ecker, David J; Sampath, Rangarajan; Lee, Chyi-Chia Richard; Turner, Maria L

2010-05-01

Pyoderma gangrenosum-like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient's culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when subcultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum-like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum-like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy.

THE FLICKER RESPONSE CONTOURS FOR GENETICALLY RELATED FISHES. II

PubMed Central

Crozier, W. J.; Wolf, Ernst

1939-01-01

The flicker response contour has been determined for several species and types of the teleosts Xiphophorus (X.) and Platypoecilius (P.) under the same conditions. The curve (F vs. log Im) is the same for representatives of each generic type, but is different for the two genera. Its duplex nature is analyzable in each instance by application of the probability integral equation to the rod and cone constituent parts. The parameters of this function provide rational measures of invariant properties of the curves, which have specific values according to the genetic constitution of the animal. The F 1 hybrids (H'') of X. montezuma x P. variatus show dominance of the X. properties with respect to cone Fmax. and σ' log I, but an intermediate value of the abscissa of inflection (τ'). The rod segment shows dominance of σ' log I from P., but an intermediate value of Fmax. and of τ'. The composite flicker curve involves the operation of two distinct assemblages of excitable elements, differing quantitatively but not qualitatively in physicochemical organization, probably only secondarily related to the histological differentiation of rods and cones because almost certainly of central nervous locus, but following different rules in hereditary determination, and therefore necessarily different in physical organization. The interpretation of the diverse behavior of the three parameters of the probability summation is discussed, particularly in relation to the physical significance of these parameters as revealed by their quantitative relations to temperature, retinal area, and light time fraction in the flash cycle, and to their interrelations in producing the decline of rod effects at higher intensities. It is stressed that in general the properties of the parameters of a chosen interpretive analytical function must be shown experimentally to possess the physical properties implied by the equation selected before the equation can be regarded as describing those invariant

Analysis of axial spatial resolution in a variable resolution x-ray cone beam CT (VRX-CBCT) system

NASA Astrophysics Data System (ADS)

Dahi, Bahram; Keyes, Gary S.; Rendon, David A.; DiBianca, Frank A.

2008-03-01

The Variable Resolution X-ray (VRX) technique has been successfully used in a Cone-Beam CT (CBCT) system to increase the spatial resolution of CT images in the transverse plane. This was achieved by tilting the Flat Panel Detector (FPD) to smaller vrx y angles in a VRX Cone Beam CT (VRX-CBCT) system. In this paper, the effect on the axial spatial resolution of CT images created by the VRX-CBCT system is examined at different vrx x angles, where vrx x is the tilting angle of the FPD about its x-axis. An amorphous silicon FPD with a CsI scintillator is coupled with a micro-focus x-ray tube to form a CBCT. The FPD is installed on a rotating frame that allows rotation of up to 90° about x and y axes of the FPD. There is no rotation about the z-axis (i.e. normal to the imaging surface). Tilting the FPD about its x-axis (i.e. decreasing the vrx x angle) reduces both the width of the line-spread function and the sampling distance by a factor of sin vrx x, thereby increasing the theoretical detector pre-sampling spatial resolution proportionately. This results in thinner CT slices that in turn help increase the axial spatial resolution of the CT images. An in-house phantom is used to measure the MTF of the reconstructed CT images at different vrx x angles.

Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics

PubMed Central

Cideciyan, Artur V.; Aleman, Tomas S.; Boye, Sanford L.; Schwartz, Sharon B.; Kaushal, Shalesh; Roman, Alejandro J.; Pang, Ji-jing; Sumaroka, Alexander; Windsor, Elizabeth A. M.; Wilson, James M.; Flotte, Terence R.; Fishman, Gerald A.; Heon, Elise; Stone, Edwin M.; Byrne, Barry J.; Jacobson, Samuel G.; Hauswirth, William W.

2008-01-01

The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both cone- and rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with <1 h in normal eyes. Cone-sensitivity recovery time was rapid. These results demonstrate dramatic, albeit imperfect, recovery of rod- and cone-photoreceptor-based vision after RPE65 gene therapy. PMID:18809924

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

PubMed

Jonsson, Kenneth B; Zahradnik, Richard; Larsson, Tobias; White, Kenneth E; Sugimoto, Toshitsugu; Imanishi, Yasuo; Yamamoto, Takehisa; Hampson, Geeta; Koshiyama, Hiroyuki; Ljunggren, Osten; Oba, Koichi; Yang, In Myung; Miyauchi, Akimitsu; Econs, Michael J; Lavigne, Jeffrey; Jüppner, Harald

2003-04-24

Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic

Genetics Home Reference: X-linked congenital stationary night blindness

MedlinePlus

... Health Conditions X-linked congenital stationary night blindness X-linked congenital stationary night blindness Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked congenital stationary night blindness is a disorder ...

Genetics Home Reference: X-linked lissencephaly with abnormal genitalia

MedlinePlus

... Health Conditions X-linked lissencephaly with abnormal genitalia X-linked lissencephaly with abnormal genitalia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked lissencephaly with abnormal genitalia (XLAG) is a ...

Genetics Home Reference: X-linked sideroblastic anemia and ataxia

MedlinePlus

... Health Conditions X-linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia and ataxia is a rare ...

Genetics Home Reference: X-linked intellectual disability, Siderius type

MedlinePlus

... Health Conditions X-linked intellectual disability, Siderius type X-linked intellectual disability, Siderius type Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked intellectual disability, Siderius type is a condition ...

X-linked Acrogigantism (X-LAG) Syndrome: Clinical Profile and Therapeutic Responses

PubMed Central

Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J.; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H.; Bours, Vincent; Liu, Pengfei; De Herder, Wouter; Pellegata, Natalia; Lupski, James R.; Daly, Adrian F.; Stratakis, Constantine A.

2015-01-01

X-linked acro-gigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and a microduplication in chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in 2 families was dominant with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2–3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight SDS score of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF-1 and prolactin, usually due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high somatostatin receptor subtype-2 expression in tumor tissue. Postoperative adjuvant pegvisomant achieved control of IGF-1 all 5 cases in which it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. PMID:25712922

Genetics Home Reference: X-linked hyper IgM syndrome

MedlinePlus

... Home Health Conditions X-linked hyper IgM syndrome X-linked hyper IgM syndrome Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked hyper IgM syndrome is a condition that ...

Non-syndromic posterior lenticonus a cause of childhood cataract: evidence for X-linked inheritance.

PubMed

Russell-Eggitt, I M

2000-12-01

When an X-linked pedigree of posterior lenticonus with cataract was identified further evidence for X-linked inheritance of this condition was sought. Forty-three cases of posterior lenticonus were identified from a database of 354 children with cataract. Two children with the X-linked syndromes of Lowe and Nance-Horan and 3 children with Fanconi syndrome have been excluded from further analysis. None of the children was deaf. None of the non-syndromic cases had microcornea. There were 38 cases of non-syndromic posterior lenticonus (approximately 11%). There were 15 children from 13 pedigrees and 23 apparently sporadic cases. Of the 106 cases on the database with unilateral cataract 15 had posterior lenticonus (approximately 14%). Eleven of 13 pedigrees were compatible with X-linked inheritance or autosomal dominant inheritance with variable expression. However, in 2 pedigrees there was father to son transmission. Posterior lenticonus is a common cause of unilateral infantile cataract, but is thought to be a rare cause of bilateral cataracts. This study suggests that posterior lenticonus is responsible for a significant proportion of childhood cataracts (approximately 14% of unilateral and approximately 9% of bilateral cases). Posterior lenticonus is generally thought to occur as a sporadic condition. This study demonstrates that there is a family history of early-onset cataract in a significant number of bilateral cases (approximately 58%).

Genotype-phenotype variations in five Spanish families with Norrie disease or X-linked FEVR.

PubMed

Riveiro-Alvarez, Rosa; Trujillo-Tiebas, Maria José; Gimenez-Pardo, Ascension; Garcia-Hoyos, Maria; Cantalapiedra, Diego; Lorda-Sanchez, Isabel; Rodriguez de Alba, Marta; Ramos, Carmen; Ayuso, Carmen

2005-09-02

Norrie disease (OMIM 310600) is a rare X-linked disorder characterized by congenital blindness in males. Approximately 40 to 50% of the cases develop deafness and mental retardation. X-linked familial exudative vitreoretinopathy (XL-FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Both X-linked disorders are due to mutations in the NDP gene, which encodes a 133 amino acid protein called Norrin, but autosomal recessive (AR) and autosomal dominant (AD) forms of FEVR have also been described. In this study, we report the molecular findings and the related phenotype in five Spanish families affected with Norrie disease or XL-FEVR due to mutations of the NDP gene. The study was conducted in 45 subjects from five Spanish families. These families were clinically diagnosed with Norrie disease or similar conditions. The three exons of the NDP gene were analyzed by automatic DNA sequencing. Haplotype analyses were also performed. Two new nonsense mutations, apart from other mutations previously described in the NDP gene, were found in those patients affected with ND or X-linked FEVR. An important genotype-phenotype variation was found in relation to the different mutations of the NDP gene. In fact, the same mutation may be responsible for different phenotypes. We speculate that there might be other molecular factors that interact in the retina with Norrin, which contribute to the resultant phenotypes.

Gluon structure function of a color dipole in the light-cone limit of lattice QCD

NASA Astrophysics Data System (ADS)

Grünewald, D.; Ilgenfritz, E.-M.; Pirner, H. J.

2009-10-01

We calculate the gluon structure function of a color dipole in near-light-cone SU(2) lattice QCD as a function of xB. The quark and antiquark are external nondynamical degrees of freedom which act as sources of the gluon string configuration defining the dipole. We compute the color dipole matrix element of transversal chromo-electric and chromo-magnetic field operators separated along a direction close to the light cone, the Fourier transform of which is the gluon structure function. As vacuum state in the pure glue sector, we use a variational ground state of the near-light-cone Hamiltonian. We derive a recursion relation for the gluon structure function on the lattice similar to the perturbative Dokshitzer-Gribov-Lipatov-Altarelli-Parisi equation. It depends on the number of transversal links assembling the Schwinger string of the dipole. Fixing the mean momentum fraction of the gluons to the “experimental value” in a proton, we compare our gluon structure function for a dipole state with four links with the next-to-leading-order MRST 2002 and the CTEQ AB-0 parametrizations at Q2=1.5GeV2. Within the systematic uncertainty we find rather good agreement. We also discuss the low xB behavior of the gluon structure function in our model calculation.

JWFront: Wavefronts and Light Cones for Kerr Spacetimes

NASA Astrophysics Data System (ADS)

Frutos Alfaro, Francisco; Grave, Frank; Müller, Thomas; Adis, Daria

2015-04-01

JWFront visualizes wavefronts and light cones in general relativity. The interactive front-end allows users to enter the initial position values and choose the values for mass and angular momentum per unit mass. The wavefront animations are available in 2D and 3D; the light cones are visualized using the coordinate systems (t, x, y) or (t, z, x). JWFront can be easily modified to simulate wavefronts and light cones for other spacetime by providing the Christoffel symbols in the program.

De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy

PubMed Central

Buena-Atienza, Elena; Rüther, Klaus; Baumann, Britta; Bergholz, Richard; Birch, David; De Baere, Elfride; Dollfus, Helene; Greally, Marie T.; Gustavsson, Peter; Hamel, Christian P.; Heckenlively, John R.; Leroy, Bart P.; Plomp, Astrid S.; Pott, Jan Willem R.; Rose, Katherine; Rosenberg, Thomas; Stark, Zornitza; Verheij, Joke B. G. M.; Weleber, Richard; Zobor, Ditta; Weisschuh, Nicole; Kohl, Susanne; Wissinger, Bernd

2016-01-01

X-linked cone dysfunction disorders such as Blue Cone Monochromacy and X-linked Cone Dystrophy are characterized by complete loss (of) or reduced L- and M- cone function due to defects in the OPN1LW/OPN1MW gene cluster. Here we investigated 24 affected males from 16 families with either a structurally intact gene cluster or at least one intact single (hybrid) gene but harbouring rare combinations of common SNPs in exon 3 in single or multiple OPN1LW and OPN1MW gene copies. We assessed twelve different OPN1LW/MW exon 3 haplotypes by semi-quantitative minigene splicing assay. Nine haplotypes resulted in aberrant splicing of ≥20% of transcripts including the known pathogenic haplotypes (i.e. ‘LIAVA’, ‘LVAVA’) with absent or minute amounts of correctly spliced transcripts, respectively. De novo formation of the ‘LIAVA’ haplotype derived from an ancestral less deleterious ‘LIAVS’ haplotype was observed in one family with strikingly different phenotypes among affected family members. We could establish intrachromosomal gene conversion in the male germline as underlying mechanism. Gene conversion in the OPN1LW/OPN1MW genes has been postulated, however, we are first to demonstrate a de novo gene conversion within the lineage of a pedigree. PMID:27339364

Genetics Home Reference: X-linked dystonia-parkinsonism

MedlinePlus

... X-linked dystonia-parkinsonism syndrome (XDP): clinical and molecular genetic analysis. Brain Pathol. 1992 Oct;2(4):287-95. Review. Citation on PubMed Kaji R, Goto S, Tamiya G, Ando S, Makino S, Lee LV. Molecular dissection and anatomical basis of dystonia: X-linked ...

Volumetric imaging of rod and cone photoreceptor structure with a combined adaptive optics-optical coherence tomography-scanning laser ophthalmoscope

NASA Astrophysics Data System (ADS)

Wells-Gray, Elaine M.; Choi, Stacey S.; Zawadzki, Robert J.; Finn, Susanna C.; Greiner, Cherry; Werner, John S.; Doble, Nathan

2018-03-01

We have designed and implemented a dual-mode adaptive optics (AO) imaging system that combines spectral domain optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) for in vivo imaging of the human retina. The system simultaneously acquires SLO frames and OCT B-scans at 60 Hz with an OCT volume acquisition time of 4.2 s. Transverse eye motion measured from the SLO is used to register the OCT B-scans to generate three-dimensional (3-D) volumes. Key optical design considerations include: minimizing system aberrations through the use of off-axis relay telescopes, conjugate pupil plane requirements, and the use of dichroic beam splitters to separate and recombine the OCT and SLO beams around the nonshared horizontal scanning mirrors. To demonstrate system performance, AO-OCT-SLO images and measurements are taken from three normal human subjects ranging in retinal eccentricity from the fovea out to 15-deg temporal and 20-deg superior. Also presented are en face OCT projections generated from the registered 3-D volumes. The ability to acquire high-resolution 3-D images of the human retina in the midperiphery and beyond has clinical importance in diseases, such as retinitis pigmentosa and cone-rod dystrophy.

Modeling the role of mid-wavelength cones in circadian responses to light

PubMed Central

Dkhissi-Benyahya, Ouria; Gronfier, Claude; De Vanssay, Wena; Flamant, Frédéric; Cooper, Howard M.

2007-01-01

Summary Non-visual responses to light, such as photic entrainment of the circadian clock, involve intrinsically light sensitive melanopsin-expressing ganglion cells as well as rod and cone photoreceptors. However, previous studies have been unable to demonstrate a specific contribution of cones in the photic control of circadian responses to light. Using a mouse model that specifically lacks mid-wavelength (MW) cones we show that these photoreceptors play a significant role in light entrainment and in phase shifting of the circadian oscillator. The contribution of MW cones is mainly observed for light exposures of short duration and towards the longer wavelength region of the spectrum, consistent with the known properties of this opsin. Modelling the contributions of the various photoreceptors stresses the importance of considering the particular spectral, temporal and irradiance response domains of the photopigments when assessing their role and contribution in circadian responses to light. PMID:17329208

Good Epidemiologic Practice in Retinitis Pigmentosa: From Phenotyping to Biobanking

PubMed Central

Chizzolini, Marzio; Galan, Alessandro; Milan, Elisabeth; Sebastiani, Adolfo; Costagliola, Ciro; Parmeggiani, Francesco

2011-01-01

Inherited retinal dystrophies, such as retinitis pigmentosa (RP), include a group of relatively rare hereditary diseases caused by mutations in genes that code for proteins involved in the maintenance and function of the photoreceptor cells (cones and rods). The different forms of RP consist of progressive neurodegenerative disorders which are generally related to various and severe limitations of visual performances. In the course of typical RP (rod-cone dystrophy), the affected individuals first experience night-blindness and/or visual field constriction (secondary to rod dysfunctions), followed by variable alterations of the central vision (due to cone damages). On the other hand, during the atypical form of RP (cone-rod dystrophy), the cone’s functionalities are prevalently disrupted in comparison with the rod’s ones. The basic diagnosis of RP relies upon the documentation of unremitting loss in photoreceptor activity by electroretinogram and/or visual field testing. The prevalence of all RP typologies is variably reported in about one case for each 3000-5000 individuals, with a total of about two millions of affected persons worldwide. The inherited retinal dystrophies are sometimes the epiphenomenon of a complex framework (syndromic RP), but more often they represent an isolated disorder (about 85-90 % of cases). Although 200 causative RP mutations have been hitherto detected in more than 100 different genes, the molecular defect is identifiable in just about the 50% of the analyzed patients with RP. Not only the RP genotypes are very heterogeneous, but also the patients with the same mutation can be affected by different phenotypic manifestations. RP can be inherited as autosomal dominant, autosomal recessive or X-linked trait, and many sporadic forms are diagnosed in patients with no affected relatives. Dissecting the clinico-genetic complexity of RP has become an attainable objective by means of large-scale research projects, in which the collaboration

Genetics Home Reference: cone-rod dystrophy

MedlinePlus

... Citation on PubMed Sergouniotis PI, McKibbin M, Robson AG, Bolz HJ, De Baere E, Müller PL, Heller ... qualified healthcare professional . About Selection Criteria for Links Data Files & API Site Map Subscribe Customer Support USA. ...

Protanomaly-without-darkened-red is deuteranopia with rods

PubMed Central

Shevell, Steven K.; Sun, Yang; Neitz, Maureen

2008-01-01

The Rayleigh match, a color match between a mixture of 545+670 nm lights and 589 nm light in modern instruments, is the definitive measurement for the diagnosis of inherited red/green color defects. All trichromats, whether normal or anomalous, have a limited range of 545+670 nm mixtures they perceive to match 589 nm: a typical color-normal match-range is about 50–55% of 670 nm in the mixture (deutan mode), while deuteranomals have a range that includes mixtures with less 670 nm than normal and protanomals a range that includes mixtures with more 670 nm than normal. Further, the matching luminance of the 589 nm light for deuteranomals is the same as for normals but for protanomals is below normal. An example of an unexpected Rayleigh match, therefore, is a match range above normal (typical of protanomaly) and a normal luminance setting for 589 nm (typical of deuteranomaly), a match that Pickford (1950) called protanomaly “when the red end of the spectrum is not darkened”. In this case, Rayleigh matching does not yield a clear diagnosis. Aside from Pickford, we are aware of only one other report of a similar observer (Pokorny and Smith, 1981); this study predated modern genetic techniques that can reveal the cone photopigment(s) in the red/green range. We recently had the opportunity to conduct genetic and psychophysical tests on such an observer. Genetic results predict he is a deuteranope. His Rayleigh match is consistent with L cones and a contribution from rods. Further, with a rod-suppressing background, his Rayleigh match is characteristic of a single L-cone photopigment (deuteranopia). PMID:18423511

Stimulus-evoked outer segment changes in rod photoreceptors

NASA Astrophysics Data System (ADS)

Zhao, Xiaohui; Thapa, Damber; Wang, Benquan; Lu, Yiming; Gai, Shaoyan; Yao, Xincheng

2016-06-01

Rod-dominated transient retinal phototropism (TRP) has been recently observed in freshly isolated mouse and frog retinas. Comparative confocal microscopy and optical coherence tomography revealed that the TRP was predominantly elicited from the rod outer segment (OS). However, the biophysical mechanism of rod OS dynamics is still unknown. Mouse and frog retinal slices, which displayed a cross-section of retinal photoreceptors and other functional layers, were used to test the effect of light stimulation on rod OSs. Time-lapse microscopy revealed stimulus-evoked conformational changes of rod OSs. In the center of the stimulated region, the length of the rod OS shrunk, while in the peripheral region, the rod OS swung toward the center region. Our experimental observation and theoretical analysis suggest that the TRP may reflect unbalanced rod disc-shape changes due to localized visible light stimulation.

Stimulus-evoked outer segment changes in rod photoreceptors

PubMed Central

Zhao, Xiaohui; Thapa, Damber; Wang, Benquan; Lu, Yiming; Gai, Shaoyan; Yao, Xincheng

2016-01-01

Abstract. Rod-dominated transient retinal phototropism (TRP) has been recently observed in freshly isolated mouse and frog retinas. Comparative confocal microscopy and optical coherence tomography revealed that the TRP was predominantly elicited from the rod outer segment (OS). However, the biophysical mechanism of rod OS dynamics is still unknown. Mouse and frog retinal slices, which displayed a cross-section of retinal photoreceptors and other functional layers, were used to test the effect of light stimulation on rod OSs. Time-lapse microscopy revealed stimulus-evoked conformational changes of rod OSs. In the center of the stimulated region, the length of the rod OS shrunk, while in the peripheral region, the rod OS swung toward the center region. Our experimental observation and theoretical analysis suggest that the TRP may reflect unbalanced rod disc-shape changes due to localized visible light stimulation. PMID:27334933

Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.

PubMed

Maugeri, A; Klevering, B J; Rohrschneider, K; Blankenagel, A; Brunner, H G; Deutman, A F; Hoyng, C B; Cremers, F P

2000-10-01

The photoreceptor cell-specific ATP-binding cassette transporter gene (ABCA4; previously denoted "ABCR") is mutated, in most patients, with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients from Germany and The Netherlands with isolated CRD. Single-strand conformation-polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans.

Converging Resonance Cones in the LAPTAG plasma

NASA Astrophysics Data System (ADS)

Katz, Cami; Ha, Chris; Gekelman, Walter; Pribyl, Patrick; Agmon, Nathan; Wise, Joe; Baker, Bob

2013-10-01

The LAPTAG laboratory is a high school outreach effort that has a 1.5m long 50 cm diameter magnetized plasma device. The plasma is produced by an ICP source (1X109 < n < 5X1011 cm-3) and has computer controlled data acquisition. Ring antennas are used to produce converging resonance cones. The experiment was performed in the quiescent plasma afterglow. The electrostatic cones were produced by rf applied to the rings (80 < f < 120 MHz), where fRF < fx-z plane where the z axis is parallel to the background field. (50G < B < 100 G). Two resonance cones were clearly measured as well as reflections from the density gradient at the plasma edge. The cone angle compares well to the theoretical value. The two focal points, far removed from the antenna are ideal locations for generating hotspots and density perturbations when the rf power is high. Graphics and movies showing the cone generation at different frequencies will be shown. Work performed at the Basic Plasma Science Facility supported by DOE and NSF.

A simple method to prevent hard X-ray-induced preheating effects inside the cone tip in indirect-drive fast ignition implosions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Dongxiao; Shan, Lianqiang; Zhou, Weimin

During fast-ignition implosions, preheating of inside the cone tip caused by hard X-rays can strongly affect the generation and transport of hot electrons in the cone. Although indirect-drive implosions have a higher implosion symmetry, they cause stronger preheating effects than direct-drive implosions. To control the preheating of the cone tip, we propose the use of indirect-drive fast-ignition targets with thicker tips. Experiments carried out at the ShenGuang-III prototype laser facility confirmed that thicker tips are effective for controlling preheating. Moreover, these results were consistent with those of 1D radiation hydrodynamic simulations.

Multiple cone pathways are involved in photic regulation of retinal dopamine.

PubMed

Qiao, Sheng-Nan; Zhang, Zhijing; Ribelayga, Christophe P; Zhong, Yong-Mei; Zhang, Dao-Qi

2016-06-30

Dopamine is a key neurotransmitter in the retina and plays a central role in the light adaptive processes of the visual system. The sole source of retinal dopamine is dopaminergic amacrine cells (DACs). We and others have previously demonstrated that DACs are activated by rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs) upon illumination. However, it is still not clear how each class of photosensitive cells generates light responses in DACs. We genetically isolated cone function in mice to specifically examine the cone-mediated responses of DACs and their neural pathways. In addition to the reported excitatory input to DACs from light-increment (ON) bipolar cells, we found that cones alternatively signal to DACs via a retrograde signalling pathway from ipRGCs. Cones also produce ON and light-decrement (OFF) inhibitory responses in DACs, which are mediated by other amacrine cells, likely driven by type 1 and type 2/3a OFF bipolar cells, respectively. Dye injections indicated that DACs had similar morphological profiles with or without ON/OFF inhibition. Our data demonstrate that cones utilize specific parallel excitatory and inhibitory circuits to modulate DAC activity and efficiently regulate dopamine release and the light-adaptive state of the retina.

A family with X-linked optic atrophy linked to the OPA2 locus Xp11.4-Xp11.2.

PubMed

Katz, Bradley J; Zhao, Yu; Warner, Judith E A; Tong, Zongzhong; Yang, Zhenglin; Zhang, Kang

2006-10-15

Autosomal dominant optic atrophy (ADOA) is the most common inherited optic atrophy. Clinical features of ADOA include a slowly progressive bilateral loss of visual acuity, constriction of peripheral visual fields, central scotomas, and color vision abnormalities. Although ADOA is the most commonly inherited optic atrophy, autosomal recessive, X-linked, mitochondrial, and sporadic forms have also been reported. Four families with X-linked optic atrophy (XLOA) were previously described. One family was subsequently linked to Xp11.4-Xp11.2 (OPA2). This investigation studied one multi-generation family with an apparently X-linked form of optic atrophy and compared their clinical characteristics with those of the previously described families, and determined whether this family was linked to the same genetic locus. Fifteen individuals in a three-generation Idaho family underwent complete eye examination, color vision testing, automated perimetry, and fundus photography. Polymorphic markers were used to genotype each individual and to determine linkage. Visual acuities ranged from 20/30 to 20/100. All affected subjects had significant optic nerve pallor. Obligate female carriers were clinically unaffected. Preliminary linkage analysis (LOD score = 1.8) revealed that the disease gene localized to the OPA2 locus on Xp11.4-Xp11.2. Four forms of inherited optic neuropathy, ADOA, autosomal recessive optic atrophy (Costeff Syndrome), Leber hereditary optic neuropathy, and Charcot-Marie-Tooth disease with optic atrophy, are associated with mitochondrial dysfunction. Future identification of the XLOA gene will reveal whether this form of optic atrophy is also associated with a mitochondrial defect. Identification of the XLOA gene will advance our understanding of the inherited optic neuropathies and perhaps suggest treatments for these diseases. An improved understanding of inherited optic neuropathies may in turn advance our understanding of acquired optic nerve diseases, such

Genetics Home Reference: alpha thalassemia X-linked intellectual disability syndrome

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... thalassemia X-linked intellectual disability syndrome Alpha thalassemia X-linked intellectual disability syndrome Printable PDF Open All ... view the expand/collapse boxes. Description Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder ...

A 40-foot static cone penetrometer

USGS Publications Warehouse

Beard, R.M.; Lee, H.J.

1982-01-01

The Navy needs a lightweight device for testing seafloor soils to sub bottom depths of 12 meters in water depths to 60 meters. To meet this need a quasistatic cone penetration device that uses water jetting to reduce friction on the cone rod has been developed. This device is called the XSP-40. The 5-ton XSP-40 stands 15 meters tall and pushes a standard 5-ton cone into the seafloor. It is remotely controlled with an electronic unit on the deck of the support vessel. All cone outputs are recorded directly as a function of penetration depth with a strip chart recorder. A full suite of gauges is provided. on the electronic unit for monitoring the XSP-40's performance during a test .. About 40 penetration tests have been performed with very good success. The XSP-40 was field tested in Norton Sound, off the west coast of Alaska. The general objective, in addition to evaluation of the device, was to gather geotechnical information on sediments that may be involved in processes potentially hazardous to offshore development. Four example penetration records are presented from gas charged sediment zones and areas near the Yukon River delta. In general it was determined that soil classification from cone data agreed well with classifications from core samples. Relative densities of the silt-sand to sandy-silt soils were usually very high. The significance of these results are discussed with respect to storm wave, liquefaction. It is concluded that the XSP-40 is a durable and reliable piece of equipment capable of achieving penetration beyond that possible when not using the water jet system.

FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.

PubMed

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-09-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. © 2016 WILEY PERIODICALS, INC.

FARVATX: FAmily-based Rare Variant Association Test for X-linked genes

PubMed Central

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H.; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-01-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease (COPD). Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. PMID:27325607

Nitrogen-doped micropore-dominant carbon derived from waste pine cone as a promising metal-free electrocatalyst for aqueous zinc/air batteries

NASA Astrophysics Data System (ADS)

Lei, Xiaoke; Wang, Mengran; Lai, Yanqing; Hu, Langtao; Wang, Hao; Fang, Zhao; Li, Jie; Fang, Jing

2017-10-01

The exploitation for highly effective and low-cost metal-free catalysts with facile and environmental friendly method for oxygen reduction reaction is still a great challenge. To find an effective method for catalyst synthesis, in this manuscript, waste biomass pine cone is employed as raw material and nitrogen-doped micropore-dominant carbon material with excellent ORR catalytic activity is successfully synthesized. The as-prepared N-doped micropore-dominant carbon possesses a high surface area of 1556 m2 g-1. In addition, this carbon electrocatalyst loaded electrode exhibits a high discharge voltage 1.07 V at the current density of 50 mA cm-2, which can be ascribed to the rich micropores and high content of pyridinic N of the prepared carbon, indicative of great potential in the application of zinc/air batteries.

Self-cleaning threaded rod spinneret for high-efficiency needleless electrospinning

NASA Astrophysics Data System (ADS)

Zheng, Gaofeng; Jiang, Jiaxin; Wang, Xiang; Li, Wenwang; Zhong, Weizheng; Guo, Shumin

2018-07-01

High-efficiency production of nanofibers is the key to the application of electrospinning technology. This work focuses on multi-jet electrospinning, in which a threaded rod electrode is utilized as the needless spinneret to achieve high-efficiency production of nanofibers. A slipper block, which fits into and moves through the threaded rod, is designed to transfer polymer solution evenly to the surface of the rod spinneret. The relative motion between the slipper block and the threaded rod electrode promotes the instable fluctuation of the solution surface, thus the rotation of threaded rod electrode decreases the critical voltage for the initial multi-jet ejection and the diameter of nanofibers. The residual solution on the surface of threaded rod is cleaned up by the moving slipper block, showing a great self-cleaning ability, which ensures the stable multi-jet ejection and increases the productivity of nanofibers. Each thread of the threaded rod electrode serves as an independent spinneret, which enhances the electric field strength and constrains the position of the Taylor cone, resulting in high productivity of uniform nanofibers. The diameter of nanofibers decreases with the increase of threaded rod rotation speed, and the productivity increases with the solution flow rate. The rotation of electrode provides an excess force for the ejection of charged jets, which also contributes to the high-efficiency production of nanofibers. The maximum productivity of nanofibers from the threaded rod spinneret is 5-6 g/h, about 250-300 times as high as that from the single-needle spinneret. The self-cleaning threaded rod spinneret is an effective way to realize continuous multi-jet electrospinning, which promotes industrial applications of uniform nanofibrous membrane.

Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia.

PubMed

Schön, Christian; Asteriti, Sabrina; Koch, Susanne; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Herms, Jochen; Seeliger, Mathias W; Cangiano, Lorenzo; Biel, Martin; Michalakis, Stylianos

2016-03-15

Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

X-linked congenital panhypopituitarism.

PubMed

Schimke, R N; Spaulding, J J; Hollowell, J G

1971-05-01

Two half brothers with panhypopituitary dwarfism are reported who have the same mother and different, unrelated fathers. The subject of hereditary panhypopituitarism is reviewed briefly. It is concluded that there are at least two forms of hereditary panhypopituitary dwarfism, one of which may be X-linked.

Occupancy of the Chromophore Binding Site of Opsin Activates Visual Transduction in Rod Photoreceptors

PubMed Central

Kefalov, Vladimir J.; Carter Cornwall, M.; Crouch, Rosalie K.

1999-01-01

The retinal analogue β-ionone was used to investigate possible physiological effects of the noncovalent interaction between rod opsin and its chromophore 11-cis retinal. Isolated salamander rod photoreceptors were exposed to bright light that bleached a significant fraction of their pigment, were allowed to recover to a steady state, and then were exposed to β-ionone. Our experiments show that in bleach-adapted rods β-ionone causes a decrease in light sensitivity and dark current and an acceleration of the dim flash photoresponse and the rate constants of guanylyl cyclase and cGMP phosphodiesterase. Together, these observations indicate that in bleach-adapted rods β-ionone activates phototransduction in the dark. Control experiments showed no effect of β-ionone in either fully dark-adapted or background light-adapted cells, indicating direct interaction of β-ionone with the free opsin produced by bleaching. We speculate that β-ionone binds specifically in the chromophore pocket of opsin to produce a complex that is more catalytically potent than free opsin alone. We hypothesize that a similar reaction may occur in the intact retina during pigment regeneration. We propose a model of rod pigment regeneration in which binding of 11-cis retinal to opsin leads to activation of the complex accompanied by a decrease in light sensitivity. The subsequent covalent attachment of retinal to opsin completely inactivates opsin and leads to the recovery of sensitivity. Our findings resolve the conflict between biochemical and physiological data concerning the effect of the occupancy of the chromophore binding site on the catalytic potency of opsin. We show that binding of β-ionone to rod opsin produces effects opposite to its previously described effects on cone opsin. We propose that this distinction is due to a fundamental difference in the interaction of rod and cone opsins with retinal, which may have implications for the different physiology of the two types of

A modified quadrupole mass spectrometer with custom RF link rods driver for remote operation

NASA Technical Reports Server (NTRS)

Tashbar, P. W.; Nisen, D. B.; Moore, W. W., Jr.

1973-01-01

A commercial quadrupole residual gas analyzer system has been upgraded for operation at extended cable lengths. Operation inside a vacuum chamber for the standard quadrupole nude head is limited to approximately 2 m from its externally located rf/dc generator because of the detuning of the rf oscillator circuits by the coaxial cable reactance. The advance of long distance remote operation inside a vacuum chamber for distances of 45 and 60 m was made possible without altering the quadrupole's rf/dc generator circuit by employing an rf link to drive the quadrupole rods. Applications of the system have been accomplished for in situ space simulation thermal/vacuum testing of sophisticated payloads.

Protanomaly without darkened red is deuteranopia with rods.

PubMed

Shevell, Steven K; Sun, Yang; Neitz, Maureen

2008-11-01

The Rayleigh match, a color match between a mixture of 545+670 nm lights and 589 nm light in modern instruments, is the definitive measurement for the diagnosis of inherited red-green color defects. All trichromats, whether normal or anomalous, have a limited range of 545+670 nm mixtures they perceive to match 589 nm: a typical color-normal match range is about 50-55% of 670 nm in the mixture (deutan mode), while deuteranomals have a range that includes mixtures with less 670 nm than normal and protanomals a range that includes mixtures with more 670 nm than normal. Further, the matching luminance of the 589 nm light for deuteranomals is the same as for normals but for protanomals is below normal. An example of an unexpected Rayleigh match, therefore, is a match range above normal (typical of protanomaly) and a normal luminance setting for 589 nm (typical of deuteranomaly), a match called protanomaly "when the red end of the spectrum is not darkened" [Pickford, R.W. (1950). Three pedigrees for color blindness. Nature, 165, 182.]. In this case, Rayleigh matching does not yield a clear diagnosis. Aside from Pickford, we are aware of only one other report of a similar observer [Pokorny, J., & Smith, V. C. (1981). A variant of red-green color defect. Vision Research, 21, 311-317]; this study predated modern genetic techniques that can reveal the cone photopigment(s) in the red-green range. We recently had the opportunity to conduct genetic and psychophysical tests on such an observer. Genetic results predict he is a deuteranope. His Rayleigh match is consistent with L cones and a contribution from rods. Further, with a rod-suppressing background, his Rayleigh match is characteristic of a single L-cone photopigment (deuteranopia).

Linkage and candidate gene analysis of X-linked familial exudative vitreoretinopathy.

PubMed

Shastry, B S; Hejtmancik, J F; Plager, D A; Hartzer, M K; Trese, M T

1995-05-20

Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disorder characterized by avascularity of the peripheral retina, retinal exudates, tractional detachment, and retinal folds. The disorder is most commonly transmitted as an autosomal dominant trait, but X-linked transmission also occurs. To initiate the process of identifying the gene responsible for the X-linked disorder, linkage analysis has been performed with three previously unreported three- or four-generation families. Two-point analysis showed linkage to MAOA (Zmax = 2.1, theta max = 0) and DXS228 (Zmax = 0.5, theta max = 0.11), and this was further confirmed by multipoint analysis with these same markers (Zmax = 2.81 at MAOA), which both lie near the gene causing Norrie disease. Molecular genetic analysis further reveals a missense mutation (R121W) in the third exon of the Norrie's disease gene that perfectly cosegregates with the disease through three generations in one family. This mutation was not detected in the unaffected family members and six normal unrelated controls, suggesting that it is likely to be the pathogenic mutation. Additionally, a polymorphic missense mutation (H127R) was detected in a severely affected patient.

An Ethyl-Nitrosourea-Induced Point Mutation in Phex Causes Exon Skipping, X-Linked Hypophosphatemia, and Rickets

PubMed Central

Carpinelli, Marina R.; Wicks, Ian P.; Sims, Natalie A.; O’Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J.; Bahlo, Melanie; Alexander, Warren S.; Hilton, Douglas J.

2002-01-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G1) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease. PMID:12414538

An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets.

PubMed

Carpinelli, Marina R; Wicks, Ian P; Sims, Natalie A; O'Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J; Bahlo, Melanie; Alexander, Warren S; Hilton, Douglas J

2002-11-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.

Rapid synaptic vesicle endocytosis in cone photoreceptors of salamander retina

PubMed Central

Van Hook, Matthew J.; Thoreson, Wallace B.

2013-01-01

Following synaptic vesicle exocytosis, neurons retrieve the fused membrane by a process of endocytosis in order to provide a supply of vesicles for subsequent release and maintain the presynaptic active zone. Rod and cone photoreceptors use a specialized structure called the synaptic ribbon that enables them to sustain high rates of neurotransmitter release. They must also employ mechanisms of synaptic vesicle endocytosis capable of keeping up with release. While much is known about endocytosis at another retinal ribbon synapse, that of the goldfish Mb1 bipolar cell, less is known about endocytosis in photoreceptors. We used capacitance recording techniques to measure vesicle membrane fusion and retrieval in photoreceptors from salamander retinal slices. We found that application of brief depolarizing steps (<100 ms) to cones evoked exocytosis followed by rapid endocytosis with a time constant ~250 ms. In some cases, the capacitance trace overshot the baseline, indicating excess endocytosis. Calcium had no effect on the time constant, but enhanced excess endocytosis resulting in a faster rate of membrane retrieval. Surprisingly, endocytosis was unaffected by blockers of dynamin, suggesting that cone endocytosis is dynamin-independent. This contrasts with synaptic vesicle endocytosis in rods, which was inhibited by the dynamin inhibitor dynasore and GTPγS introduced through the patch pipette, suggesting that the two photoreceptor types employ distinct pathways for vesicle retrieval. The fast kinetics of synaptic vesicle endocytosis in photoreceptors likely enables these cells to maintain a high rate of transmitter release, allowing them to faithfully signal changes in illumination to second-order neurons. PMID:23238726

X-linked juvenile retinoschisis in a consanguineous family: phenotypic variability and report of a homozygous female patient.

PubMed

Gliem, Martin; Holz, Frank G; Stöhr, Heidi; Weber, Bernhard H F; Charbel Issa, Peter

2014-12-01

To describe the phenotypic variability in a consanguineous family with genetically confirmed X-linked retinoschisis. Five patients, including one homozygous female, were characterized by clinical examination, optical coherence tomography, fundus autofluorescence, mapping of macular pigment optical density, electroretinography, and DNA testing. The 36-year-old male index patient showed a ring of enhanced autofluorescence and outer retinal atrophy on optical coherence tomography. Electroretinography testing revealed a reduced a/b ratio. His mother presented with a central atrophic retina with markedly reduced autofluorescence signal and a surrounding ring of enhanced autofluorescence. The 40-year-old brother of the index patient and his 2 sons showed characteristic signs for X-linked retinoschisis, including retinal schisis and a reduced a/b ratio. Genetic testing revealed a c.293C>A mutation in the RS1 gene in all affected family members while the mother of the index patient was homozygous for this mutation. X-linked retinoschisis can present with a wide phenotypic variability. Here, detailed family history and genetic testing established the diagnosis of X-linked retinoschisis despite striking differences in phenotypic presentation in affected subjects, homozygosity of one affected female, and seemingly dominant inheritance in three subsequent generations because of multiple consanguinity.

Mutations in the ABCA4 (ABCR) Gene Are the Major Cause of Autosomal Recessive Cone-Rod Dystrophy

PubMed Central

Maugeri, Alessandra; Klevering, B. Jeroen; Rohrschneider, Klaus; Blankenagel, Anita; Brunner, Han G.; Deutman, August F.; Hoyng, Carel B.; Cremers, Frans P. M.

2000-01-01

The photoreceptor cell–specific ATP-binding cassette transporter gene (ABCA4; previously denoted “ABCR”) is mutated in most patients with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients with isolated CRD, all from Germany and The Netherlands . Single-strand conformation–polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans. PMID:10958761

Simultaneous Occurence of an Autosomal Dominant Inherited MSX1 Mutation and an X-linked Recessive Inherited EDA Mutation in One Chinese Family with Non-syndromic Oligodontia.

PubMed

Zhang, Xiao Xia; Wong, Sing Wai; Han, Dong; Feng, Hai Lan

2015-01-01

To describe the simultaneous occurence of an autosomal dominant inherited MSX1 mutation and an X-linked recessive inherited EDA mutation in one Chinese family with nonsyndromic oligodontia. Clinical data of characteristics of tooth agenesis were collected. MSX1 and EDA gene mutations were detected in a Chinese family of non-syndromic oligodontia. Mild hypodontia in the parents and severe oligodontia in the son was recorded. A novel missense heterozygous mutation c.517C>A (p.Arg173Ser) was detected in the MSX1 gene in the boy and the father. A homozygous missense mutation c.1001G>A (p.Arg334His) was detected in the EDA gene in the boy and the same mutant occurred heterozygously in the mother. Simultaneous occurence of two different gene mutations with different inheritence patterns, which both caused oligodontia, which occurred in one subject and in one family, was reported.

Phenotype-genotype correlations in X linked retinitis pigmentosa.

PubMed Central

Kaplan, J; Pelet, A; Martin, C; Delrieu, O; Aymé, S; Bonneau, D; Briard, M L; Hanauer, A; Larget-Piet, L; Lefrançois, P

1992-01-01

Retinitis pigmentosa (RP) represents a group of clinically heterogeneous retinal degenerations in which all modes of inheritance have been described. We have previously found two different clinical profiles in X linked RP as a function of age and mode of onset. The first clinical form has very early onset with severe myopia. The second form starts later with night blindness with mild myopia or none. At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome. In order to contribute to phenotype-genotype correlations in X linked RP, we tested the hypothesis that the two clinical profiles could be accounted for by the two different gene loci. The present study provides evidence for linkage of the clinical form with early myopia as the onset symptom with the RP2 gene (pairwise linkage to DXS255: Z = 3.13 at theta = 0), while the clinical form with later night blindness as the onset symptom is linked to the RP3 gene (pairwise linkage to OTC: Z = 4.16 at theta = 0). Images PMID:1357178

Sex-specific silencing of X-linked genes by Xist RNA

PubMed Central

Gayen, Srimonta; Maclary, Emily; Hinten, Michael; Kalantry, Sundeep

2016-01-01

X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of XΔTsixY male cells displayed ectopic Xist RNA coating compared with XΔTsixX female cells. This increase reflected the inability of XΔTsixY cells to efficiently silence X-linked genes compared with XΔTsixX cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in XΔTsixX female cells relative to XΔTsixY male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating XΔTsixY and 39,XΔTsix (XΔTsixO) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sex-specific differences. Because XΔTsixX female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active XΔTsix X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing. PMID:26739568

Stages of rootless cone formation observed within the Raudhólar cone group, Iceland

NASA Astrophysics Data System (ADS)

Fitch, E. P.; Hamilton, C.; Fagents, S. A.; Thordarson, T.

2013-12-01

Secondary (rootless) cones form when lava interacts explosively with water contained in the substrate, and represent a largely degassed, end-member system that can elucidate mechanisms of magma-water interactions in the absence of primary degassing-induced fragmentation. Rootless cones are well documented in Iceland. The Raudhólar rootless cone group, located within the ~5200-year-old Ellidaá lava flow on the south-eastern outskirts of Reykjavík, was extensively quarried during the Second World War and now provides excellent cross-sections through the tephra sequences. Taking advantage of this exposure, we performed detailed stratigraphic, grain-size, and componentry analyses, which suggest that the energetics of rootless explosions vary substantially during cone formation. The lower unit contains the most substrate sediment and is characterized by dilute pyroclastic density current deposits. The middle unit is dominated by a succession of bed-pairs, each containing a finer-grained lower layer and coarser-grained upper layer. In the upper unit, the succession grades into a welded section that caps the cone. The abundance of substrate sediment generally decreases upwards within the cone, which suggests that the efficiency of lava-substrate mixing decreased with time. In addition, clast size generally increases upwards within the cone, implying that the fragmentation energy also decreased as the rootless eruption progressed. Both lines of evidence suggest that the explosions decreased in intensity with time, likely due to the depletion of available groundwater. However, alternating fine- and coarse-grained beds imply cycles of increased and decreased fragmentation efficiency, which we attribute to groundwater recharge and depletion during the event. Therefore, this study presents a detailed look at rootless cone formation and provides the foundation for future work on this important, yet understudied, system.

Influence of sampling window size and orientation on parafoveal cone packing density

PubMed Central

Lombardo, Marco; Serrao, Sebastiano; Ducoli, Pietro; Lombardo, Giuseppe

2013-01-01

We assessed the agreement between sampling windows of different size and orientation on packing density estimates in images of the parafoveal cone mosaic acquired using a flood-illumination adaptive optics retinal camera. Horizontal and vertical oriented sampling windows of different size (320x160 µm, 160x80 µm and 80x40 µm) were selected in two retinal locations along the horizontal meridian in one eye of ten subjects. At each location, cone density tended to decline with decreasing sampling area. Although the differences in cone density estimates were not statistically significant, Bland-Altman plots showed that the agreement between cone density estimated within the different sampling window conditions was moderate. The percentage of the preferred packing arrangements of cones by Voronoi tiles was slightly affected by window size and orientation. The results illustrated the high importance of specifying the size and orientation of the sampling window used to derive cone metric estimates to facilitate comparison of different studies. PMID:24009995

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes

PubMed Central

Krasovec, Marc; Filatov, Dmitry A.

2018-01-01

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (πx = 0.016; πaut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex. PMID:29751495

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes.

PubMed

Krasovec, Marc; Nevado, Bruno; Filatov, Dmitry A

2018-05-03

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (π x = 0.016; π aut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex.

Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy

PubMed Central

Méjécase, Cécile; Bertelli, Matteo; Terray, Angélique; Michiels, Christelle; Condroyer, Christel; Fouquet, Stéphane; Sadoun, Maxime; Clérin, Emmanuelle; Liu, Binqian; Léveillard, Thierry; Goureau, Olivier; Sahel, José-Alain; Audo, Isabelle

2017-01-01

We identified herein additional patients with rod-cone dystrophy (RCD) displaying mutations in KIZ, encoding the ciliary centrosomal protein kizuna and performed functional characterization of the respective protein in human fibroblasts and of its mouse ortholog PLK1S1 in the retina. Mutation screening was done by targeted next generation sequencing and subsequent Sanger sequencing validation. KIZ mRNA levels were assessed on blood and serum-deprived human fibroblasts from a control individual and a patient, compound heterozygous for the c.52G>T (p.Glu18*) and c.119_122del (p.Lys40Ilefs*14) mutations in KIZ. KIZ localization, documentation of cilium length and immunoblotting were performed in these two fibroblast cell lines. In addition, PLK1S1 immunolocalization was conducted in mouse retinal cryosections and isolated rod photoreceptors. Analyses of additional RCD patients enabled the identification of two homozygous mutations in KIZ, the known c.226C>T (p.Arg76*) mutation and a novel variant, the c.3G>A (p.Met1?) mutation. Albeit the expression levels of KIZ were three-times lower in the patient than controls in whole blood cells, further analyses in control- and mutant KIZ patient-derived fibroblasts unexpectedly revealed no significant difference between the two genotypes. Furthermore, the averaged monocilia length in the two fibroblast cell lines was similar, consistent with the preserved immunolocalization of KIZ at the basal body of the primary cilia. Analyses in mouse retina and isolated rod photoreceptors showed PLK1S1 localization at the base of the photoreceptor connecting cilium. In conclusion, two additional patients with mutations in KIZ were identified, further supporting that defects in KIZ/PLK1S1, detected at the basal body of the primary cilia in fibroblasts, and the photoreceptor connecting cilium in mouse, respectively, are involved in RCD. However, albeit the mutations were predicted to lead to nonsense mediated mRNA decay, we could not detect

The X-ray emitting gas in poor clusters with central dominant galaxies

NASA Technical Reports Server (NTRS)

Kriss, G. A.; Cioffi, D. F.; Canizares, C. R.

1983-01-01

The 12 clusters detected in the present study by the Einstein Observatory's X-ray imaging proportional counter show X-ray emission centered on the dominant galaxy in all cases. Comparison of the deduced distribution of binding mass with the light distribution of the central galaxies of four clusters indicates that the mass/luminosity ratio rises to over 200 solar masses/solar luminosity in the galaxy halos. These halos must therefore, like the clusters themselves, posses dark matter. The X-ray data clearly show that the dominant galaxies sit at the bottoms of the poor cluster gravitational potential wells, suggesting a similar origin for dominant galaxies in poor and rich clusters, perhaps through the merger and cannibalism of cluster galaxies. It is the luminosity of the distended cD envelope that reflects the relative wealth of the cluster environment.

Optimization of a rod pinch diode radiography source at 2.3 MV

NASA Astrophysics Data System (ADS)

Menge, P. R.; Johnson, D. L.; Maenchen, J. E.; Rovang, D. C.; Oliver, B. V.; Rose, D. V.; Welch, D. R.

2003-08-01

Rod pinch diodes have shown considerable capability as high-brightness flash x-ray sources for penetrating dynamic radiography. The rod pinch diode uses a small diameter (0.4-2 mm) anode rod extended through a cathode aperture. When properly configured, the electron beam born off of the aperture edge can self-insulate and pinch onto the tip of the rod creating an intense, small x-ray source. Sandia's SABRE accelerator (2.3 MV, 40 Ω, 70 ns) has been utilized to optimize the source experimentally by maximizing the figure of merit (dose/spot diameter2) and minimizing the diode impedance droop. Many diode parameters have been examined including rod diameter, rod length, rod material, cathode aperture diameter, cathode thickness, power flow gap, vacuum quality, and severity of rod-cathode misalignment. The configuration producing the greatest figure of merit uses a 0.5 mm diameter gold rod, a 6 mm rod extension beyond the cathode aperture (diameter=8 mm), and a 10 cm power flow gap to produce up to 3.5 rad (filtered dose) at 1 m from a 0.85 mm x-ray on-axis spot (1.02 mm at 3° off axis). The resultant survey of parameter space has elucidated several physics issues that are discussed.

Macular hole in juvenile X-linked retinoschisis.

PubMed

Al-Swaina, Nayef; Nowilaty, Sawsan R

2013-10-01

An 18 year-old male with no antecedent of trauma, systemic syndrome or myopia was referred for surgical treatment of a full thickness macular hole in the left eye. A more careful inspection revealed discrete foveal cystic changes in the fellow eye and subtle peripheral depigmented retinal pigment epithelial changes in both eyes. A spectral-domain optical coherence tomography (SD-OCT) scan confirmed, in addition to the full thickness macular hole in the left eye, microcystic spaces in the nuclear layers of both retinae. The diagnosis of X-linked retinoschisis was confirmed with a full field electroretinogram displaying the typical negative ERG. Macular holes are uncommon in the young and those complicating X-linked retinoschisis are rare. This report highlights the importance of investigating the presence of a macular hole in a young patient and illustrates the clinical and SD-OCT clues beyond the foveal center which led to the correct diagnosis of X-linked juvenile retinoschisis.

Comparison of Online 6 Degree-of-Freedom Image Registration of Varian TrueBeam Cone-Beam CT and BrainLab ExacTrac X-Ray for Intracranial Radiosurgery.

PubMed

Li, Jun; Shi, Wenyin; Andrews, David; Werner-Wasik, Maria; Lu, Bo; Yu, Yan; Dicker, Adam; Liu, Haisong

2017-06-01

The study was aimed to compare online 6 degree-of-freedom image registrations of TrueBeam cone-beam computed tomography and BrainLab ExacTrac X-ray imaging systems for intracranial radiosurgery. Phantom and patient studies were performed on a Varian TrueBeam STx linear accelerator (version 2.5), which is integrated with a BrainLab ExacTrac imaging system (version 6.1.1). The phantom study was based on a Rando head phantom and was designed to evaluate isocenter location dependence of the image registrations. Ten isocenters at various locations representing clinical treatment sites were selected in the phantom. Cone-beam computed tomography and ExacTrac X-ray images were taken when the phantom was located at each isocenter. The patient study included 34 patients. Cone-beam computed tomography and ExacTrac X-ray images were taken at each patient's treatment position. The 6 degree-of-freedom image registrations were performed on cone-beam computed tomography and ExacTrac, and residual errors calculated from cone-beam computed tomography and ExacTrac were compared. In the phantom study, the average residual error differences (absolute values) between cone-beam computed tomography and ExacTrac image registrations were 0.17 ± 0.11 mm, 0.36 ± 0.20 mm, and 0.25 ± 0.11 mm in the vertical, longitudinal, and lateral directions, respectively. The average residual error differences in the rotation, roll, and pitch were 0.34° ± 0.08°, 0.13° ± 0.09°, and 0.12° ± 0.10°, respectively. In the patient study, the average residual error differences in the vertical, longitudinal, and lateral directions were 0.20 ± 0.16 mm, 0.30 ± 0.18 mm, 0.21 ± 0.18 mm, respectively. The average residual error differences in the rotation, roll, and pitch were 0.40°± 0.16°, 0.17° ± 0.13°, and 0.20° ± 0.14°, respectively. Overall, the average residual error differences were <0.4 mm in the translational directions and <0.5° in the rotational directions. ExacTrac X-ray image

Developing an Outcome Measure With High Luminance for Optogenetics Treatment of Severe Retinal Degenerations and for Gene Therapy of Cone Diseases.

PubMed

Cideciyan, Artur V; Roman, Alejandro J; Jacobson, Samuel G; Yan, Boyuan; Pascolini, Michele; Charng, Jason; Pajaro, Simone; Nirenberg, Sheila

2016-06-01

To present stimuli with varied sizes, colors, and patterns over a large range of luminance. The filter bar used in scotopic MP1 was replaced with a custom slide-in tray that introduces light from an external projector driven by an additional computer. MP1 software was modified to provide retinal tracking information to the computer driving the projector. Retinal tracking performance was evaluated by imaging the system input and the output simultaneously with a high-speed video system. Spatial resolution was measured with achromatic and chromatic grating/background combinations over scotopic and photopic ranges. The range of retinal illuminance achievable by the modification was up to 6.8 log photopic Trolands (phot-Td); however, in the current work, only a lower range over -4 to +3 log phot-Td was tested in human subjects. Optical magnification was optimized for low-vision testing with gratings from 4.5 to 0.2 cyc/deg. In normal subjects, spatial resolution driven by rods, short wavelength-sensitive (S-) cones, and long/middle wavelength-sensitive (L/M-) cones was obtained by the choice of adapting conditions and wavelengths of grating and background. Data from a patient with blue cone monochromacy was used to confirm mediation. The modified MP1 can be developed into an outcome measure for treatments in patients with severe retinal degeneration, very low vision, and abnormal eye movements such as those for whom treatment with optogenetics is planned, as well as for patients with cone disorders such as blue cone monochromacy for whom treatment with gene therapy is planned to improve L/M-cone function above a normal complement of rod and S-cone function.

Hurricane track forecast cones from fluctuations

PubMed Central

Meuel, T.; Prado, G.; Seychelles, F.; Bessafi, M.; Kellay, H.

2012-01-01

Trajectories of tropical cyclones may show large deviations from predicted tracks leading to uncertainty as to their landfall location for example. Prediction schemes usually render this uncertainty by showing track forecast cones representing the most probable region for the location of a cyclone during a period of time. By using the statistical properties of these deviations, we propose a simple method to predict possible corridors for the future trajectory of a cyclone. Examples of this scheme are implemented for hurricane Ike and hurricane Jimena. The corridors include the future trajectory up to at least 50 h before landfall. The cones proposed here shed new light on known track forecast cones as they link them directly to the statistics of these deviations. PMID:22701776

X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

PubMed

Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H; Bours, Vincent; Liu, Pengfei; W de Herder, Wouter; Pellegata, Natalia; Lupski, James R; Daly, Adrian F; Stratakis, Constantine A

2015-06-01

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. © 2015 Society for Endocrinology.

Examining the Self-Assembly of Rod-Coil Block Copolymers via Physics Based Polymer Models and Polarized X-Ray Scattering

NASA Astrophysics Data System (ADS)

Hannon, Adam; Sunday, Daniel; Windover, Donald; Liman, Christopher; Bowen, Alec; Khaira, Gurdaman; de Pablo, Juan; Delongchamp, Dean; Kline, R. Joseph

Photovoltaics, flexible electronics, and stimuli-responsive materials all require enhanced methodology to examine their nanoscale molecular orientation. The mechanical, electronic, optical, and transport properties of devices made from these materials are all a function of this orientation. The polymer chains in these materials are best modeled as semi-flexible to rigid rods. Characterizing the rigidity and molecular orientation of these polymers non-invasively is currently being pursued by using polarized resonant soft X-ray scattering (P-RSoXS). In this presentation, we show recent work on implementing such a characterization process using a rod-coil block copolymer system in the rigid-rod limit. We first demonstrate how we have used physics based models such as self-consistent field theory (SCFT) in non-polarized RSoXS work to fit scattering profiles for thin film coil-coil PS- b-PMMA block copolymer systems. We then show by using a wormlike chain partition function in the SCFT formulism to model the rigid-rod block, the methodology can be used there as well to extract the molecular orientation of the rod block from a simulated P-RSoXS experiment. The results from the work show the potential of the technique to extract thermodynamic and morphological sample information.

[Neurophysiological basis and clinical tests for assessment of X-linked color vision deficiencies in school children].

PubMed

Rigaudière, F; Leid, J; Viénot, F; Le Gargasson, J-F

2006-01-01

Vision screening of school children at 5-6 years of age must include color vision screening. X-linked dyschromatopsia is the most frequent disorder affecting 8% of boys and 0.4% of girls. This paper presents the physiology of these deficiencies caused by an alteration of the spectral absorption properties of one of the cone pigments (protanomalous or deuteranomalous trichromats) or the absence of one of the pigments (protanopia or deuteranopia), the most frequent. Absence of two of the pigments (blue cone monochromacy) is very rare and differs from achromatopsia. The physiological basis of the main tests for easy clinical screening are presented. Testing methods designed for children are reviewed. The Ishihara test is the most widely used screening test specific for congenital color defects. If the plates are correctly read, the child has normal color vision. If not, arrangement tests such as Panel D 15 and desaturated Panel D 15 tests can be used to diagnose the type of the defect (protan or deutan) and grade the degree of color deficiency according to a strategy adapted to children. Examples of results are presented for each axis along which caps are confused, providing a quick and easy preliminary diagnosis. Early detection of color vision malfunction in children allows parents and teachers to make necessary adjustments to the teaching methods for appropriate learning.

Novel mutations of RPGR in Chinese retinitis pigmentosa patients and the genotype-phenotype correlation.

PubMed

Yang, Liping; Yin, Xiaobei; Feng, Lina; You, Debo; Wu, Lemeng; Chen, Ningning; Li, Aijun; Li, Genlin; Ma, Zhizhong

2014-01-01

X-linked Retinitis Pigmentosa (XLRP) accounts for 10-20% of all RP cases, and represents the most severe subtype of this disease. Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the most common causes of XLRP, accounting for over 70-75% of all XLRP cases. In this work, we analyzed all the exons of RPGR gene with Sanger sequencing in seven Chinese XLRP families, two of these with a provisional diagnosis of adRP but without male-to-male transmission. Three novel deletions (c.2233_34delAG; c.2236_37delGA and c.2403_04delAG) and two known nonsense mutations (c.851C→G and c.2260G→T) were identified in five families. Two novel deletions (c.2233_34delAG and c.2236_37delGA) resulted in the same frame shift (p.E746RfsX22), created similar phenotype in Family 3 and 4. The novel deletion (c.2403_04delAG; p.E802GfsX31) resulted in both XLRP and x-linked cone-rod dystrophy within the male patients of family 5, which suggested the presence of either genetic or environmental modifiers, or both, play a substantial role in disease expression. Genotype-phenotype correlation analysis suggested that (1) both patients and female carriers with mutation in Exon 8 (Family 1) manifest more severe disease than did those with ORF15 mutations (Family 2&3&4); (2) mutation close to downstream of ORF15 (Family 5) demonstrate the early preferential loss of cone function with moderate loss of rod function.

Evidence for Phex haploinsufficiency in murine X-linked hypophosphatemia.

PubMed

Wang, L; Du, L; Ecarot, B

1999-04-01

Mutations in the PHEX gene (phosphate-regulating gene with homology to endopeptidases on the X-chromosome) are responsible for X-linked hypophosphatemia (HYP). We previously reported the full-length coding sequence of murine Phex cDNA and provided evidence of Phex expression in bone and tooth. Here, we report the cloning of the entire 3.5-kb 3'UTR of the Phex gene, yielding a total of 6248 bp for the Phex transcript. Southern blot and RT-PCR analyses revealed that the 3' end of the coding sequence and the 3'UTR of the Phex gene, spanning exons 16 to 22, are deleted in Hyp, the mouse model for HYP. Northern blot analysis of bone revealed lack of expression of stable Phex mRNA from the mutant allele and expression of Phex transcripts from the wild-type allele in Hyp heterozygous females. Expression of the Phex protein in heterozygotes was confirmed by Western analysis with antibodies raised against a COOH-terminal peptide of the mouse Phex protein. Taken together, these results indicate that the dominant pattern of Hyp inheritance in mice is due to Phex haploinsufficiency.

Usher syndrome type 1–associated cadherins shape the photoreceptor outer segment

PubMed Central

Parain, Karine; Aghaie, Asadollah; Picaud, Serge

2017-01-01

Usher syndrome type 1 (USH1) causes combined hearing and sight defects, but how mutations in USH1 genes lead to retinal dystrophy in patients remains elusive. The USH1 protein complex is associated with calyceal processes, which are microvilli of unknown function surrounding the base of the photoreceptor outer segment. We show that in Xenopus tropicalis, these processes are connected to the outer-segment membrane by links composed of protocadherin-15 (USH1F protein). Protocadherin-15 deficiency, obtained by a knockdown approach, leads to impaired photoreceptor function and abnormally shaped photoreceptor outer segments. Rod basal outer disks displayed excessive outgrowth, and cone outer segments were curved, with lamellae of heterogeneous sizes, defects also observed upon knockdown of Cdh23, encoding cadherin-23 (USH1D protein). The calyceal processes were virtually absent in cones and displayed markedly reduced F-actin content in rods, suggesting that protocadherin-15–containing links are essential for their development and/or maintenance. We propose that calyceal processes, together with their associated links, control the sizing of rod disks and cone lamellae throughout their daily renewal. PMID:28495838

Usher syndrome type 1-associated cadherins shape the photoreceptor outer segment.

PubMed

Schietroma, Cataldo; Parain, Karine; Estivalet, Amrit; Aghaie, Asadollah; Boutet de Monvel, Jacques; Picaud, Serge; Sahel, José-Alain; Perron, Muriel; El-Amraoui, Aziz; Petit, Christine

2017-06-05

Usher syndrome type 1 (USH1) causes combined hearing and sight defects, but how mutations in USH1 genes lead to retinal dystrophy in patients remains elusive. The USH1 protein complex is associated with calyceal processes, which are microvilli of unknown function surrounding the base of the photoreceptor outer segment. We show that in Xenopus tropicalis , these processes are connected to the outer-segment membrane by links composed of protocadherin-15 (USH1F protein). Protocadherin-15 deficiency, obtained by a knockdown approach, leads to impaired photoreceptor function and abnormally shaped photoreceptor outer segments. Rod basal outer disks displayed excessive outgrowth, and cone outer segments were curved, with lamellae of heterogeneous sizes, defects also observed upon knockdown of Cdh23 , encoding cadherin-23 (USH1D protein). The calyceal processes were virtually absent in cones and displayed markedly reduced F-actin content in rods, suggesting that protocadherin-15-containing links are essential for their development and/or maintenance. We propose that calyceal processes, together with their associated links, control the sizing of rod disks and cone lamellae throughout their daily renewal. © 2017 Schietroma et al.

Chromosomal rearrangement segregating with adrenoleukodystrophy: associated changes in color vision.

PubMed Central

Alpern, M; Sack, G H; Krantz, D H; Jenness, J; Zhang, H; Moser, H W

1993-01-01

A patient from a large kindred with adrenoleukodystrophy showed profound disturbance of color ordering, color matching, increment thresholds, and luminosity. Except for color matching, his performance was similar to blue-cone "monochromacy," an X chromosome-linked recessive retinal dystrophy in which color vision is dichromatic, mediated by the visual pigments of rods and short-wave-sensitive cones. Color matching, however, indicated that an abnormal rudimentary visual pigment was also present. This may reflect the presence of a recombinant visual pigment protein or altered regulation of residual pigment genes, due to DNA changes--deletion of the long-wave pigment gene and reorganized sequences 5' to the pigment gene cluster--that segregate with the metabolic defect in this kindred. PMID:8415729

Contemporary Medical and Surgical Management of X-linked Hypophosphatemic Rickets.

PubMed

Sharkey, Melinda S; Grunseich, Karl; Carpenter, Thomas O

2015-07-01

X-linked hypophosphatemia is an inheritable disorder of renal phosphate wasting that clinically manifests with rachitic bone pathology. X-linked hypophosphatemia is frequently misdiagnosed and mismanaged. Optimized medical therapy is the cornerstone of treatment. Even with ideal medical management, progressive bony deformity may develop in some children and adults. Medical treatment is paramount to the success of orthopaedic surgical procedures in both children and adults with X-linked hypophosphatemia. Successful correction of complex, multiapical bone deformities found in patients with X-linked hypophosphatemia is possible with careful surgical planning and exacting surgical technique. Multiple methods of deformity correction are used, including acute and gradual correction. Treatment of some pediatric bony deformity with guided growth techniques may be possible. Copyright 2015 by the American Academy of Orthopaedic Surgeons.

Longleaf Pine Cone Crops and Climate: A Possible Link

Treesearch

Neil Pederson; John S. Kush; Ralph S. Meldahl; William D. Bayer

1999-01-01

The physiological development of longieaf pine seed extends over three calendar years. The duration of this process may explain the reason for infrequent seed crops. Infrequent crops cause problems for those interested in natural regeneration. Longleaf pine cone crops have been monitored on the Escambia Experimental Forest (EEF) in Brewton, AL since 1958. Weather data...

The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility*

PubMed Central

Ding, Xi-Qin; Thapa, Arjun; Ma, Hongwei; Xu, Jianhua; Elliott, Michael H.; Rodgers, Karla K.; Smith, Marci L.; Wang, Jin-Shan; Pittler, Steven J.; Kefalov, Vladimir J.

2016-01-01

Cone photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in cone phototransduction, which is a process essential for daylight vision, color vision, and visual acuity. Mutations in the cone channel subunits CNGA3 and CNGB3 are associated with human cone diseases, including achromatopsia, cone dystrophies, and early onset macular degeneration. Mutations in CNGB3 alone account for 50% of reported cases of achromatopsia. This work investigated the role of CNGB3 in cone light response and cone channel structural stability. As cones comprise only 2–3% of the total photoreceptor population in the wild-type mouse retina, we used Cngb3−/−/Nrl−/− mice with CNGB3 deficiency on a cone-dominant background in our study. We found that, in the absence of CNGB3, CNGA3 was able to travel to the outer segments, co-localize with cone opsin, and form tetrameric complexes. Electroretinogram analyses revealed reduced cone light response amplitude/sensitivity and slower response recovery in Cngb3−/−/Nrl−/− mice compared with Nrl−/− mice. Absence of CNGB3 expression altered the adaptation capacity of cones and severely compromised function in bright light. Biochemical analysis demonstrated that CNGA3 channels lacking CNGB3 were more resilient to proteolysis than CNGA3/CNGB3 channels, suggesting a hindered structural flexibility. Thus, CNGB3 regulates cone light response kinetics and the channel structural flexibility. This work advances our understanding of the biochemical and functional role of CNGB3 in cone photoreceptors. PMID:26893377

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails.

PubMed

Jin, Ai-Hua; Israel, Mathilde R; Inserra, Marco C; Smith, Jennifer J; Lewis, Richard J; Alewood, Paul F; Vetter, Irina; Dutertre, Sébastien

2015-07-22

Some venomous cone snails feed on small fishes using an immobilizing combination of synergistic venom peptides that target Kv and Nav channels. As part of this envenomation strategy, δ-conotoxins are potent ichtyotoxins that enhance Nav channel function. δ-Conotoxins belong to an ancient and widely distributed gene superfamily, but any evolutionary link from ancestral worm-eating cone snails to modern piscivorous species has not been elucidated. Here, we report the discovery of SuVIA, a potent vertebrate-active δ-conotoxin characterized from a vermivorous cone snail (Conus suturatus). SuVIA is equipotent at hNaV1.3, hNaV1.4 and hNaV1.6 with EC50s in the low nanomolar range. SuVIA also increased peak hNaV1.7 current by approximately 75% and shifted the voltage-dependence of activation to more hyperpolarized potentials from -15 mV to -25 mV, with little effect on the voltage-dependence of inactivation. Interestingly, the proximal venom gland expression and pain-inducing effect of SuVIA in mammals suggest that δ-conotoxins in vermivorous cone snails play a defensive role against higher order vertebrates. We propose that δ-conotoxins originally evolved in ancestral vermivorous cones to defend against larger predators including fishes have been repurposed to facilitate a shift to piscivorous behaviour, suggesting an unexpected underlying mechanism for this remarkable evolutionary transition. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

PubMed Central

Jin, Ai-Hua; Israel, Mathilde R.; Inserra, Marco C.; Smith, Jennifer J.; Lewis, Richard J.; Alewood, Paul F.; Vetter, Irina; Dutertre, Sébastien

2015-01-01

Some venomous cone snails feed on small fishes using an immobilizing combination of synergistic venom peptides that target Kv and Nav channels. As part of this envenomation strategy, δ-conotoxins are potent ichtyotoxins that enhance Nav channel function. δ-Conotoxins belong to an ancient and widely distributed gene superfamily, but any evolutionary link from ancestral worm-eating cone snails to modern piscivorous species has not been elucidated. Here, we report the discovery of SuVIA, a potent vertebrate-active δ-conotoxin characterized from a vermivorous cone snail (Conus suturatus). SuVIA is equipotent at hNaV1.3, hNaV1.4 and hNaV1.6 with EC50s in the low nanomolar range. SuVIA also increased peak hNaV1.7 current by approximately 75% and shifted the voltage-dependence of activation to more hyperpolarized potentials from –15 mV to –25 mV, with little effect on the voltage-dependence of inactivation. Interestingly, the proximal venom gland expression and pain-inducing effect of SuVIA in mammals suggest that δ-conotoxins in vermivorous cone snails play a defensive role against higher order vertebrates. We propose that δ-conotoxins originally evolved in ancestral vermivorous cones to defend against larger predators including fishes have been repurposed to facilitate a shift to piscivorous behaviour, suggesting an unexpected underlying mechanism for this remarkable evolutionary transition. PMID:26156767

Rod Electroretinograms Elicited by Silent Substitution Stimuli from the Light-Adapted Human Eye

PubMed Central

Maguire, John; Parry, Neil R. A.; Kremers, Jan; Kommanapalli, Deepika; Murray, Ian J.; McKeefry, Declan J.

2016-01-01

Purpose To demonstrate that silent substitution stimuli can be used to generate electroretinograms (ERGs) that effectively isolate rod photoreceptor function in humans without the need for dark adaptation, and that this approach constitutes a viable alternative to current clinical standard testing protocols. Methods Rod-isolating and non-isolating sinusoidal flicker stimuli were generated on a 4 primary light-emitting diode (LED) Ganzfeld stimulator to elicit ERGs from participants with normal and compromised rod function who had not undergone dark-adaptation. Responses were subjected to Fourier analysis, and the amplitude and phase of the fundamental were used to examine temporal frequency and retinal illuminance response characteristics. Results Electroretinograms elicited by rod-isolating silent substitution stimuli exhibit low-pass temporal frequency response characteristics with an upper response limit of 30 Hz. Responses are optimal between 5 and 8 Hz and between 10 and 100 photopic trolands (Td). There is a significant correlation between the response amplitudes obtained with the silent substitution method and current standard clinical protocols. Analysis of signal-to-noise ratios reveals significant differences between subjects with normal and compromised rod function. Conclusions Silent substitution provides an effective method for the isolation of human rod photoreceptor function in subjects with normal as well as compromised rod function when stimuli are used within appropriate parameter ranges. Translational Relevance This method of generating rod-mediated ERGs can be achieved without time-consuming periods of dark adaptation, provides improved isolation of rod- from cone-based activity, and will lead to the development of faster clinical electrophysiologic testing protocols with improved selectivity. PMID:27617180

Genetics Home Reference: immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

MedlinePlus

... Health Conditions IPEX syndrome Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome Printable PDF Open All Close All ... expand/collapse boxes. Description Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome primarily affects males and is ...

Developing an Outcome Measure With High Luminance for Optogenetics Treatment of Severe Retinal Degenerations and for Gene Therapy of Cone Diseases

PubMed Central

Cideciyan, Artur V.; Roman, Alejandro J.; Jacobson, Samuel G.; Yan, Boyuan; Pascolini, Michele; Charng, Jason; Pajaro, Simone; Nirenberg, Sheila

2016-01-01

Purpose To present stimuli with varied sizes, colors, and patterns over a large range of luminance. Methods The filter bar used in scotopic MP1 was replaced with a custom slide-in tray that introduces light from an external projector driven by an additional computer. MP1 software was modified to provide retinal tracking information to the computer driving the projector. Retinal tracking performance was evaluated by imaging the system input and the output simultaneously with a high-speed video system. Spatial resolution was measured with achromatic and chromatic grating/background combinations over scotopic and photopic ranges. Results The range of retinal illuminance achievable by the modification was up to 6.8 log photopic Trolands (phot-Td); however, in the current work, only a lower range over −4 to +3 log phot-Td was tested in human subjects. Optical magnification was optimized for low-vision testing with gratings from 4.5 to 0.2 cyc/deg. In normal subjects, spatial resolution driven by rods, short wavelength-sensitive (S-) cones, and long/middle wavelength-sensitive (L/M-) cones was obtained by the choice of adapting conditions and wavelengths of grating and background. Data from a patient with blue cone monochromacy was used to confirm mediation. Conclusions The modified MP1 can be developed into an outcome measure for treatments in patients with severe retinal degeneration, very low vision, and abnormal eye movements such as those for whom treatment with optogenetics is planned, as well as for patients with cone disorders such as blue cone monochromacy for whom treatment with gene therapy is planned to improve L/M-cone function above a normal complement of rod and S-cone function. PMID:27309625

Retinal photoreceptors and visual pigments in Boa constrictor imperator.

PubMed

Sillman, A J; Johnson, J L; Loew, E R

2001-09-01

The photoreceptors of Boa constrictor, a boid snake of the subfamily Boinae, were examined with scanning electron microscopy and microspectrophotometry. The retina of B. constrictor is duplex but highly dominated by rods, cones comprising 11% of the photoreceptor population. The rather tightly packed rods have relatively long outer segments with proximal ends that are somewhat tapered. There are two morphologically distinct, single cones. The most common cone by far has a large inner segment and a relatively stout outer segment. The second cone, seen only infrequently, has a substantially smaller inner segment and a finer outer segment. The visual pigments of B. constrictor are virtually identical to those of the pythonine boid, Python regius. Three different visual pigments are present, all based on vitamin A(1.) The visual pigment of the rods has a wavelength of peak absorbance (lambda(max)) at 495 +/- 2 nm. The visual pigment of the more common, large cone has a lambda(max) at 549 +/- 1 nm. The small, rare cone contains a visual pigment with lambda(max) at 357 +/- 2 nm, providing the snake with sensitivity in the ultraviolet. We suggest that B. constrictor might employ UV sensitivity to locate conspecifics and/or to improve hunting efficiency. The data indicate that wavelength discrimination above 430 nm would not be possible without some input from the rods. Copyright 2001 Wiley-Liss, Inc.

β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.

PubMed

Hayflick, Susan J; Kruer, Michael C; Gregory, Allison; Haack, Tobias B; Kurian, Manju A; Houlden, Henry H; Anderson, James; Boddaert, Nathalie; Sanford, Lynn; Harik, Sami I; Dandu, Vasuki H; Nardocci, Nardo; Zorzi, Giovanna; Dunaway, Todd; Tarnopolsky, Mark; Skinner, Steven; Holden, Kenton R; Frucht, Steven; Hanspal, Era; Schrander-Stumpel, Connie; Mignot, Cyril; Héron, Delphine; Saunders, Dawn E; Kaminska, Margaret; Lin, Jean-Pierre; Lascelles, Karine; Cuno, Stephan M; Meyer, Esther; Garavaglia, Barbara; Bhatia, Kailash; de Silva, Rajith; Crisp, Sarah; Lunt, Peter; Carey, Martyn; Hardy, John; Meitinger, Thomas; Prokisch, Holger; Hogarth, Penelope

2013-06-01

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene.

PubMed

Christie, P T; Harding, B; Nesbit, M A; Whyte, M P; Thakker, R V

2001-08-01

X-linked hypophosphatemia is commonly caused by mutations of the coding region of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approximately one third of X-linked hypophosphatemia patients who may harbor defects in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-linked hypophosphatemia patients in whom coding region mutations had been excluded, for intronic mutations that may lead to mRNA splicing abnormalities, by the use of lymphoblastoid RNA and RT-PCRs. One X-linked hypophosphatemia patient was found to have 3 abnormally large transcripts, resulting from 51-bp, 100-bp, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a mutation (g to t) at position +1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrences of the 3 pseudoexons. This represents the first report of PHEX pseudoexons and reveals further the diversity of genetic abnormalities causing X-linked hypophosphatemia.

Craniofacial morphometric analysis of individuals with X-linked hypohidrotic ectodermal dysplasia.

PubMed

Goodwin, Alice F; Larson, Jacinda R; Jones, Kyle B; Liberton, Denise K; Landan, Maya; Wang, Zhifeng; Boekelheide, Anne; Langham, Margaret; Mushegyan, Vagan; Oberoi, Snehlata; Brao, Rosalie; Wen, Timothy; Johnson, Ramsey; Huttner, Kenneth; Grange, Dorothy K; Spritz, Richard A; Hallgrímsson, Benedikt; Jheon, Andrew H; Klein, Ophir D

2014-09-01

Hypohidrotic ectodermal dysplasia (HED) is the most prevalent type of ectodermal dysplasia (ED). ED is an umbrella term for a group of syndromes characterized by missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. The X-linked recessive (XL), autosomal recessive (AR), and autosomal dominant (AD) types of HED are caused by mutations in the genes encoding ectodysplasin (EDA1), EDA receptor (EDAR), or EDAR-associated death domain (EDARADD). Patients with HED have a distinctive facial appearance, yet a quantitative analysis of the HED craniofacial phenotype using advanced three-dimensional (3D) technologies has not been reported. In this study, we characterized craniofacial morphology in subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) by use of 3D imaging and geometric morphometrics (GM), a technique that uses defined landmarks to quantify size and shape in complex craniofacial morphologies. We found that the XLHED craniofacial phenotype differed significantly from controls. Patients had a smaller and shorter face with a proportionally longer chin and midface, prominent midfacial hypoplasia, a more protrusive chin and mandible, a narrower and more pointed nose, shorter philtrum, a narrower mouth, and a fuller and more rounded lower lip. Our findings refine the phenotype of XLHED and may be useful both for clinical diagnosis of XLHED and to extend understanding of the role of EDA in craniofacial development.

Measurements in a Transitioning Cone Boundary Layer at Freestream Mach 3.5

NASA Technical Reports Server (NTRS)

King, Rudolph A.; Chou, Amanda; Balakumar, Ponnampalam; Owens, Lewis R.; Kegerise, Michael A.

2016-01-01

An experimental study was conducted in the Supersonic Low-Disturbance Tunnel to investigate naturally-occurring instabilities in a supersonic boundary layer on a 7 deg half- angle cone. All tests were conducted with a nominal freestream Mach number of M(sub infinity) = 3:5, total temperature of T(sub 0) = 299:8 K, and unit Reynolds numbers of Re(sub infinity) x 10(exp -6) = 9:89, 13.85, 21.77, and 25.73 m(exp -1). Instability measurements were acquired under noisy- ow and quiet- ow conditions. Measurements were made to document the freestream and the boundary-layer edge environment, to document the cone baseline flow, and to establish the stability characteristics of the transitioning flow. Pitot pressure and hot-wire boundary- layer measurements were obtained using a model-integrated traverse system. All hot- wire results were single-point measurements and were acquired with a sensor calibrated to mass ux. For the noisy-flow conditions, excellent agreement for the growth rates and mode shapes was achieved between the measured results and linear stability theory (LST). The corresponding N factor at transition from LST is N 3:9. The stability measurements for the quiet-flow conditions were limited to the aft end of the cone. The most unstable first-mode instabilities as predicted by LST were successfully measured, but this unstable first mode was not the dominant instability measured in the boundary layer. Instead, the dominant instabilities were found to be the less-amplified, low-frequency disturbances predicted by linear stability theory, and these instabilities grew according to linear theory. These low-frequency unstable disturbances were initiated by freestream acoustic disturbances through a receptivity process that is believed to occur near the branch I locations of the cone. Under quiet-flow conditions, the boundary layer remained laminar up to the last measurement station for the largest Re1, implying a transition N factor of N greater than 8:5.

Diversity of Color Vision: Not All Australian Marsupials Are Trichromatic

PubMed Central

Ebeling, Wiebke; Natoli, Riccardo C.; Hemmi, Jan M.

2010-01-01

Color vision in marsupials has recently emerged as a particularly interesting case among mammals. It appears that there are both dichromats and trichromats among closely related species. In contrast to primates, marsupials seem to have evolved a different type of trichromacy that is not linked to the X-chromosome. Based on microspectrophotometry and retinal whole-mount immunohistochemistry, four trichromatic marsupial species have been described: quokka, quenda, honey possum, and fat-tailed dunnart. It has, however, been impossible to identify the photopigment of the third cone type, and genetically, all evidence so far suggests that all marsupials are dichromatic. The tammar wallaby is the only Australian marsupial to date for which there is no evidence of a third cone type. To clarify whether the wallaby is indeed a dichromat or trichromatic like other Australian marsupials, we analyzed the number of cone types in the “dichromatic” wallaby and the “trichromatic” dunnart. Employing identical immunohistochemical protocols, we confirmed that the wallaby has only two cone types, whereas 20–25% of cones remained unlabeled by S- and LM-opsin antibodies in the dunnart retina. In addition, we found no evidence to support the hypothesis that the rod photopigment (rod opsin) is expressed in cones which would have explained the absence of a third cone opsin gene. Our study is the first comprehensive and quantitative account of color vision in Australian marsupials where we now know that an unexpected diversity of different color vision systems appears to have evolved. PMID:21151905

Impaired plasticity of macrophages in X-linked adrenoleukodystrophy.

PubMed

Weinhofer, Isabelle; Zierfuss, Bettina; Hametner, Simon; Wagner, Magdalena; Popitsch, Niko; Machacek, Christian; Bartolini, Barbara; Zlabinger, Gerhard; Ohradanova-Repic, Anna; Stockinger, Hannes; Köhler, Wolfgang; Höftberger, Romana; Regelsberger, Günther; Forss-Petter, Sonja; Lassmann, Hans; Berger, Johannes

2018-05-30

X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses

Liquid Crystalline Assembly of Coil-Rod-Coil Molecules with Lateral Methyl Groups into 3-D Hexagonal and Tetragonal Assemblies

PubMed Central

Wang, Zhuoshi; Lan, Yu; Zhong, Keli; Liang, Yongri; Chen, Tie; Jin, Long Yi

2014-01-01

In this paper, we report the synthesis and self-assembly behavior of coil-rod-coil molecules, consisting of three biphenyls linked through a vinylene unit as a conjugated rod segment and poly(ethylene oxide) (PEO) with a degree of polymerization (DP) of 7, 12 and 17, incorporating lateral methyl groups between the rod and coil segments as the coil segment. Self-organized investigation of these molecules by means of differential scanning calorimetry (DSC), thermal polarized optical microscopy (POM) and X-ray diffraction (XRD) reveals that the lateral methyl groups attached to the surface of rod and coil segments, dramatically influence the self-assembling behavior in the liquid-crystalline mesophase. Molecule 1 with a relatively short PEO coil length (DP = 7) self-assembles into rectangular and oblique 2-dimensional columnar assemblies, whereas molecules 2 and 3 with DP of 12 and 17 respectively, spontaneously self-organize into unusual 3-dimensional hexagonal close-packed or body-centered tetragonal assemblies. PMID:24699045

Nano-cone resistive memory for ultralow power operation.

PubMed

Kim, Sungjun; Jung, Sunghun; Kim, Min-Hwi; Kim, Tae-Hyeon; Bang, Suhyun; Cho, Seongjae; Park, Byung-Gook

2017-03-24

SiN x -based nano-structure resistive memory is fabricated by fully silicon CMOS compatible process integration including particularly designed anisotropic etching for the construction of a nano-cone silicon bottom electrode (BE). Bipolar resistive switching characteristics have significantly reduced switching current and voltage and are demonstrated in a nano-cone BE structure, as compared with those in a flat BE one. We have verified by systematic device simulations that the main cause of reduction in the performance parameters is the high electric field being more effectively concentrated at the tip of the cone-shaped BE. The greatly improved nonlinearity of the nano-cone resistive memory cell will be beneficial in the ultra-high-density crossbar array.

Development of a Cone Penetrometer for Measuring Spectral Characteristics of Soils in Situ

NASA Technical Reports Server (NTRS)

Lee, Landris T., Jr.; Malone, Philip G.

1993-01-01

A patent was recently granted to the U.S. Army for an adaptation of a soil cone penetrometer that can be used to measure the spectral characteristics (fluorescence or reflectance) of soils adjacent to the penetrometer rod. The system can use a variety of light sources and spectral analytical equipment. A laser induced fluorescence measuring system has proven to be of immediate use in mapping the distribution of oil contaminated soil at waste disposal and oil storage areas. The fiber optic adaptation coupled with a cone penetrometer permits optical characteristics of the in-situ soil to be measured rapidly, safely, and inexpensively. The fiber optic cone penetrometer can be used to gather spectral data to a depth of approximately 25 to 30 m even in dense sands or stiff clays and can investigate 300 m of soil per day. Typical detection limits for oil contamination in sand is on the order of several hundred parts per million.

Cone arrestin binding to JNK3 and Mdm2: conformational preference and localization of interaction sites

PubMed Central

Song, Xiufeng; Gurevich, Eugenia V.; Gurevich, Vsevolod V.

2008-01-01

Arrestins are multi-functional regulators of G protein-coupled receptors. Receptor-bound arrestins interact with >30 remarkably diverse proteins and redirect the signaling to G protein-independent pathways. The functions of free arrestins are poorly understood, and the interaction sites of the non-receptor arrestin partners are largely unknown. In this study, we show that cone arrestin, the least studied member of the family, binds c-Jun N-terminal kinase (JNK3) and Mdm2 and regulates their subcellular distribution. Using arrestin mutants with increased or reduced structural flexibility, we demonstrate that arrestin in all conformations binds JNK3 comparably, whereas Mdm2 preferentially binds cone arrestin ‘frozen’ in the basal state. To localize the interaction sites, we expressed separate N- and C-domains of cone and rod arrestins and found that individual domains bind JNK3 and remove it from the nucleus as efficiently as full-length proteins. Thus, the arrestin binding site for JNK3 includes elements in both domains with the affinity of partial sites on individual domains sufficient for JNK3 relocalization. N-domain of rod arrestin binds Mdm2, which localizes its main interaction site to this region. Comparable binding of JNK3 and Mdm2 to four arrestin subtypes allowed us to identify conserved residues likely involved in these interactions. PMID:17680991

Genetics Home Reference: X-linked spondyloepiphyseal dysplasia tarda

MedlinePlus

... Educational Resources (6 links) Cincinnati Children's Hospital: Coxa Vera Disease InfoSearch: Spondyloepiphyseal dysplasia tarda X-linked Johns ... Free article on PubMed Central Savarirayan R, Thompson E, Gécz J. Spondyloepiphyseal dysplasia tarda (SEDL, MIM #313400). ...

Tissue inhibitor of metalloproteinases 1 enhances rod survival in the rd1 mouse retina.

PubMed

Kim, Hwa Sun; Vargas, Andrew; Eom, Yun Sung; Li, Justin; Yamamoto, Kyra L; Craft, Cheryl Mae; Lee, Eun-Jin

2018-01-01

Retinitis pigmentosa (RP), an inherited retinal degenerative disease, is characterized by a progressive loss of rod photoreceptors followed by loss of cone photoreceptors. Previously, when tissue inhibitor of metalloproteinase 1 (TIMP1), a key extracellular matrix (ECM) regulator that binds to and inhibits activation of Matrix metallopeptidase 9 (MMP9) was intravitreal injected into eyes of a transgenic rhodopsin rat model of RP, S334ter-line3, we discovered cone outer segments are partially protected. In parallel, we reported that a specific MMP9 and MMP2 inhibitor, SB-3CT, interferes with mechanisms leading to rod photoreceptor cell death in an MMP9 dependent manner. Here, we extend our initial rat studies to examine the potential of TIMP1 as a treatment in retinal degeneration by investigating neuroprotective effects in a classic mouse retinal degeneration model, rdPde6b-/- (rd1). The results clearly demonstrate that intravitreal injections of TIMP1 produce extended protection to delay rod photoreceptor cell death. The mean total number of rods in whole-mount retinas was significantly greater in TIMP-treated rd1 retinas (postnatal (P) 30, P35 (P<0.0001) and P45 (P<0.05) than in saline-treated rd1 retinas. In contrast, SB-3CT did not delay rod cell death, leading us to further investigate alternative pathways that do not involve MMPs. In addition to inducing phosphorylated ERK1/2, TIMP1 significantly reduces BAX activity and delays attenuation of the outer nuclear layer (ONL). Physiological responses using scotopic electroretinograms (ERG) reveal b-wave amplitudes from TIMP1-treated retinas are significantly greater than from saline-treated rd1 retinas (P<0.05). In later degenerative stages of rd1 retinas, photopic b-wave amplitudes from TIMP1-treated rd1 retinas are significantly larger than from saline-treated rd1 retinas (P<0.05). Our findings demonstrate that TIMP1 delays photoreceptor cell death. Furthermore, this study provides new insights into how TIMP1

Mutational Survey of the PHEX Gene in Patients with X-linked Hypophosphatemic Rickets

PubMed Central

Ichikawa, Shoji; Traxler, Elizabeth A.; Estwick, Selina A.; Curry, Leah R.; Johnson, Michelle L.; Sorenson, Andrea H.; Imel, Erik A.; Econs, Michael J.

2008-01-01

X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. XLH is caused by inactivating mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). In this study, we sequenced the PHEX gene in subjects from 26 kindreds who were clinically diagnosed with XLH. Sequencing revealed 18 different mutations, of which thirteen have not been reported previously. In addition to deletions, splice site mutations, and missense and nonsense mutations, a rare point mutation in the 3’-untranslated region (3’-UTR) was identified as a novel cause of XLH. In summary, we identified a wide spectrum of mutations in the PHEX gene. Our data, in accord with those of others, indicate that there is no single predominant PHEX mutation responsible for XLH. PMID:18625346

Cone biopsy

MedlinePlus

... grade cone biopsy; High-grade cone biopsy; Carcinoma in situ-cone biopsy; CIS - cone biopsy; ASCUS - cone biopsy; ... marked dysplasia CIN III -- severe dysplasia to carcinoma in situ Abnormal results may also be due to cervical ...

siRNAs from an X-linked satellite repeat promote X-chromosome recognition in Drosophila melanogaster.

PubMed

Menon, Debashish U; Coarfa, Cristian; Xiao, Weimin; Gunaratne, Preethi H; Meller, Victoria H

2014-11-18

Highly differentiated sex chromosomes create a lethal imbalance in gene expression in one sex. To accommodate hemizygosity of the X chromosome in male fruit flies, expression of X-linked genes increases twofold. This is achieved by the male- specific lethal (MSL) complex, which modifies chromatin to increase expression. Mutations that disrupt the X localization of this complex decrease the expression of X-linked genes and reduce male survival. The mechanism that restricts the MSL complex to X chromatin is not understood. We recently reported that the siRNA pathway contributes to localization of the MSL complex, raising questions about the source of the siRNAs involved. The X-linked 1.688 g/cm(3) satellite related repeats (1.688(X) repeats) are restricted to the X chromosome and produce small RNA, making them an attractive candidate. We tested RNA from these repeats for a role in dosage compensation and found that ectopic expression of single-stranded RNAs from 1.688(X) repeats enhanced the male lethality of mutants with defective X recognition. In contrast, expression of double-stranded hairpin RNA from a 1.688(X) repeat generated abundant siRNA and dramatically increased male survival. Consistent with improved survival, X localization of the MSL complex was largely restored in these males. The striking distribution of 1.688(X) repeats, which are nearly exclusive to the X chromosome, suggests that these are cis-acting elements contributing to identification of X chromatin.

Rapid Retinal Release from a Cone Visual Pigment Following Photoactivation*

PubMed Central

Chen, Min-Hsuan; Kuemmel, Colleen; Birge, Robert R.; Knox, Barry E.

2012-01-01

As part of the visual cycle, the retinal chromophore in both rod and cone visual pigments undergoes reversible Schiff base hydrolysis and dissociation following photobleaching. We characterized light-activated retinal release from a short-wavelength sensitive cone pigment (VCOP) in 0.1% dodecyl maltoside using fluorescence spectroscopy. The half-time (t1/2) of retinal release from VCOP was 7.1 s, 250-fold faster than rhodopsin. VCOP exhibited pH-dependent release kinetics, with the t1/2 decreasing from 23 s to 4 s with pH 4.1 to 8, respectively. However, the Arrhenius activation energy (Ea) for VCOP derived from kinetic measurements between 4° and 20°C was 17.4 kcal/mol, similar to 18.5 kcal/mol for rhodopsin. There was a small kinetic isotope (D2O) effect in VCOP, but less than that observed in rhodopsin. Mutation of the primary Schiff base counterion (VCOPD108A) produced a pigment with an unprotonated chromophore (⌊max = 360 nm) and dramatically slowed (t1/2 ~ 6.8 min) light-dependent retinal release. Using homology modeling, a VCOP mutant with two substitutions (S85D/ D108A) was designed to move the counterion one alpha helical turn into the transmembrane region from the native position. This double mutant had a UV-visible absorption spectrum consistent with a protonated Schiff base (⌊max = 420 nm). Moreover, VCOPS85D/D108A mutant had retinal release kinetics (t1/2 = 7 s) and Ea (18 kcal/mol) similar to the native pigment exhibiting no pH-dependence. By contrast, the single mutant VCOPS85D had a ~3-fold decrease in retinal release rate compared to the native pigment. Photoactivated VCOPD108A had kinetics comparable to a rhodopsin counterion mutant, RhoE113Q, both requiring hydroxylamine to fully release retinal. These results demonstrate that the primary counterion of cone visual pigments is necessary for efficient Schiff base hydrolysis. We discuss how the large differences in retinal release rates between rod and cone visual pigments arise, not from

Development of burnup dependent fuel rod model in COBRA-TF

NASA Astrophysics Data System (ADS)

Yilmaz, Mine Ozdemir

The purpose of this research was to develop a burnup dependent fuel thermal conductivity model within Pennsylvania State University, Reactor Dynamics and Fuel Management Group (RDFMG) version of the subchannel thermal-hydraulics code COBRA-TF (CTF). The model takes into account first, the degradation of fuel thermal conductivity with high burnup; and second, the fuel thermal conductivity dependence on the Gadolinium content for both UO2 and MOX fuel rods. The modified Nuclear Fuel Industries (NFI) model for UO2 fuel rods and Duriez/Modified NFI Model for MOX fuel rods were incorporated into CTF and fuel centerline predictions were compared against Halden experimental test data and FRAPCON-3.4 predictions to validate the burnup dependent fuel thermal conductivity model in CTF. Experimental test cases from Halden reactor fuel rods for UO2 fuel rods at Beginning of Life (BOL), through lifetime without Gd2O3 and through lifetime with Gd 2O3 and a MOX fuel rod were simulated with CTF. Since test fuel rod and FRAPCON-3.4 results were based on single rod measurements, CTF was run for a single fuel rod surrounded with a single channel configuration. Input decks for CTF were developed for one fuel rod located at the center of a subchannel (rod-centered subchannel approach). Fuel centerline temperatures predicted by CTF were compared against the measurements from Halden experimental test data and the predictions from FRAPCON-3.4. After implementing the new fuel thermal conductivity model in CTF and validating the model with experimental data, CTF model was applied to steady state and transient calculations. 4x4 PWR fuel bundle configuration from Purdue MOX benchmark was used to apply the new model for steady state and transient calculations. First, one of each high burnup UO2 and MOX fuel rods from 4x4 matrix were selected to carry out single fuel rod calculations and fuel centerline temperatures predicted by CTF/TORT-TD were compared against CTF /TORT-TD /FRAPTRAN

Genetics Home Reference: X-linked agammaglobulinemia

MedlinePlus

... Sep;104(3):221-30. Citation on PubMed Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. 2001 Apr ... Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): ...

Three-Phase Coexistence in Colloidal Rod-Plate Mixtures.

PubMed

Woolston, Phillip; van Duijneveldt, Jeroen S

2015-09-01

Aqueous suspensions of clay particles, such as montmorillonite (MMT) platelets and sepiolite (Sep) rods, tend to form gels at concentrations around 1 vol %. For Sep rods, adsorbing sodium polyacrylate to the surface allows for an isotropic-nematic phase separation to be seen instead. Here, MMT is added to such Sep suspensions, resulting in a complex phase behavior. Across a range of clay concentrations, separation into three phases is observed: a lower, nematic phase dominated by Sep rods, a MMT-rich middle layer, which is weakly birefringent and probably a gel, and a dilute top phase. Analysis of phase volumes suggests that the middle layer may contain as much as 6 vol % MMT.

Improving x-ray fluorescence signal for benchtop polychromatic cone-beam x-ray fluorescence computed tomography by incident x-ray spectrum optimization: A Monte Carlo study

PubMed Central

Manohar, Nivedh; Jones, Bernard L.; Cho, Sang Hyun

2014-01-01

Purpose: To develop an accurate and comprehensive Monte Carlo (MC) model of an experimental benchtop polychromatic cone-beam x-ray fluorescence computed tomography (XFCT) setup and apply this MC model to optimize incident x-ray spectrum for improving production/detection of x-ray fluorescence photons from gold nanoparticles (GNPs). Methods: A detailed MC model, based on an experimental XFCT system, was created using the Monte Carlo N-Particle (MCNP) transport code. The model was validated by comparing MC results including x-ray fluorescence (XRF) and scatter photon spectra with measured data obtained under identical conditions using 105 kVp cone-beam x-rays filtered by either 1 mm of lead (Pb) or 0.9 mm of tin (Sn). After validation, the model was used to investigate the effects of additional filtration of the incident beam with Pb and Sn. Supplementary incident x-ray spectra, representing heavier filtration (Pb: 2 and 3 mm; Sn: 1, 2, and 3 mm) were computationally generated and used with the model to obtain XRF/scatter spectra. Quasimonochromatic incident x-ray spectra (81, 85, 90, 95, and 100 keV with 10 keV full width at half maximum) were also investigated to determine the ideal energy for distinguishing gold XRF signal from the scatter background. Fluorescence signal-to-dose ratio (FSDR) and fluorescence-normalized scan time (FNST) were used as metrics to assess results. Results: Calculated XRF/scatter spectra for 1-mm Pb and 0.9-mm Sn filters matched (r ≥ 0.996) experimental measurements. Calculated spectra representing additional filtration for both filter materials showed that the spectral hardening improved the FSDR at the expense of requiring a much longer FNST. In general, using Sn instead of Pb, at a given filter thickness, allowed an increase of up to 20% in FSDR, more prominent gold XRF peaks, and up to an order of magnitude decrease in FNST. Simulations using quasimonochromatic spectra suggested that increasing source x-ray energy, in the

Improving x-ray fluorescence signal for benchtop polychromatic cone-beam x-ray fluorescence computed tomography by incident x-ray spectrum optimization: a Monte Carlo study.

PubMed

Manohar, Nivedh; Jones, Bernard L; Cho, Sang Hyun

2014-10-01

To develop an accurate and comprehensive Monte Carlo (MC) model of an experimental benchtop polychromatic cone-beam x-ray fluorescence computed tomography (XFCT) setup and apply this MC model to optimize incident x-ray spectrum for improving production/detection of x-ray fluorescence photons from gold nanoparticles (GNPs). A detailed MC model, based on an experimental XFCT system, was created using the Monte Carlo N-Particle (MCNP) transport code. The model was validated by comparing MC results including x-ray fluorescence (XRF) and scatter photon spectra with measured data obtained under identical conditions using 105 kVp cone-beam x-rays filtered by either 1 mm of lead (Pb) or 0.9 mm of tin (Sn). After validation, the model was used to investigate the effects of additional filtration of the incident beam with Pb and Sn. Supplementary incident x-ray spectra, representing heavier filtration (Pb: 2 and 3 mm; Sn: 1, 2, and 3 mm) were computationally generated and used with the model to obtain XRF/scatter spectra. Quasimonochromatic incident x-ray spectra (81, 85, 90, 95, and 100 keV with 10 keV full width at half maximum) were also investigated to determine the ideal energy for distinguishing gold XRF signal from the scatter background. Fluorescence signal-to-dose ratio (FSDR) and fluorescence-normalized scan time (FNST) were used as metrics to assess results. Calculated XRF/scatter spectra for 1-mm Pb and 0.9-mm Sn filters matched (r ≥ 0.996) experimental measurements. Calculated spectra representing additional filtration for both filter materials showed that the spectral hardening improved the FSDR at the expense of requiring a much longer FNST. In general, using Sn instead of Pb, at a given filter thickness, allowed an increase of up to 20% in FSDR, more prominent gold XRF peaks, and up to an order of magnitude decrease in FNST. Simulations using quasimonochromatic spectra suggested that increasing source x-ray energy, in the investigated range of 81-100 ke

Test of the X(3872) structure in antiproton-nucleus collisions

NASA Astrophysics Data System (ADS)

Larionov, Alexei; Strikman, Mark; Bleicher, Marcus

2016-05-01

The present day experimental data on the X(3872) decays do not allow us to make clear conclusions about the dominant structure of this state. We discuss here an alternative way to study its structure by means of the two-step D¯* (or D) production in p ¯A reactions. If this process is mediated by X(3872), the characteristic narrow peaks of the D¯* (or D) distributions in the light cone momentum fraction at small transverse momenta will appear. This would unambiguously signal the DD¯* + c.c. molecular composition of the X(3872) state.

Cone-beam volume CT mammographic imaging: feasibility study

NASA Astrophysics Data System (ADS)

Chen, Biao; Ning, Ruola

2001-06-01

X-ray projection mammography, using a film/screen combination or digital techniques, has proven to be the most effective imaging modality for early detection of breast cancer currently available. However, the inherent superimposition of structures makes small carcinoma (a few millimeters in size) difficult to detect in the occultation case or in dense breasts, resulting in a high false positive biopsy rate. The cone-beam x-ray projection based volume imaging using flat panel detectors (FPDs) makes it possible to obtain three-dimensional breast images. This may benefit diagnosis of the structure and pattern of the lesion while eliminating hard compression of the breast. This paper presents a novel cone-beam volume CT mammographic imaging protocol based on the above techniques. Through computer simulation, the key issues of the system and imaging techniques, including the x-ray imaging geometry and corresponding reconstruction algorithms, x-ray characteristics of breast tissues, x-ray setting techniques, the absorbed dose estimation and the quantitative effect of x-ray scattering on image quality, are addressed. The preliminary simulation results support the proposed cone-beam volume CT mammographic imaging modality in respect to feasibility and practicability for mammography. The absorbed dose level is comparable to that of current two-view mammography and would not be a prominent problem for this imaging protocol. Compared to traditional mammography, the proposed imaging protocol with isotropic spatial resolution will potentially provide significantly better low contrast detectability of breast tumors and more accurate location of breast lesions.

Effects of molecular chirality on self-assembly and switching in liquid crystals at the cross-over between rod-like and bent shapes.

PubMed

Ocak, Hale; Poppe, Marco; Bilgin-Eran, Belkız; Karanlık, Gürkan; Prehm, Marko; Tschierske, Carsten

2016-09-21

A bent-core compound derived from a 4-cyanoresorcinol core unit with two terephthalate based rod-like wings and carrying chiral 3,7-dimethyloctyloxy side chains has been synthesized in racemic and enantiomerically pure form and characterized by polarizing microscopy, differential scanning calorimetry, X-ray diffraction and electro-optical investigations to study the influence of molecular chirality on the superstructural chirality and polar order in lamellar liquid crystalline phases. Herein we demonstrate that the coupling of molecular chirality with superstructural layer chirality in SmCsPF domain phases (forming energetically distinct diastereomeric pairs) can fix the tilt direction and thus stabilize synpolar order, leading to bistable ferroelectric switching in the SmC* phases of the (S)-enantiomer, whereas tristable modes determine the switching of the racemate. Moreover, the mechanism of electric field induced molecular reorganization changes from a rotation around the molecular long axis in the racemate to a rotation on the tilt-cone for the (S)-enantiomer. At high temperature the enantiomer behaves like a rod-like molecule with a chirality induced ferroelectric SmC* phase and an electroclinic effect in the SmA'* phase. At reduced temperature sterically induced polarization, due to the bent molecular shape, becomes dominating, leading to much higher polarization values, thus providing access to high polarization ferroelectric materials with weakly bent compounds having only "weakly chiral" stereogenic units. Moreover, the field induced alignment of the SmCsPF(()*()) domains gives rise to a special kind of electroclinic effect appearing even in the absence of molecular chirality. Comparison with related compounds indicates that the strongest effects of chirality appear for weakly bent molecules with a relatively short coherence length of polar order, whereas for smectic phases with long range polar order the effects of the interlayer interfaces can override

Integrity of the Cone Photoreceptor Mosaic in Oligocone Trichromacy

PubMed Central

Rha, Jungtae; Dees, Elise W.; Baraas, Rigmor C.; Wagner-Schuman, Melissa L.; Mollon, John D.; Dubis, Adam M.; Andersen, Mette K. G.; Rosenberg, Thomas; Larsen, Michael; Moore, Anthony T.

2011-01-01

Purpose. Oligocone trichromacy (OT) is an unusual cone dysfunction syndrome characterized by reduced visual acuity, mild photophobia, reduced amplitude of the cone electroretinogram with normal rod responses, normal fundus appearance, and normal or near-normal color vision. It has been proposed that these patients have a reduced number of normal functioning cones (oligocone). This paper has sought to evaluate the integrity of the cone photoreceptor mosaic in four patients previously described as having OT. Methods. Retinal images were obtained from two brothers (13 and 15 years) and two unrelated subjects, one male (47 years) and one female (24 years). High-resolution images of the cone mosaic were obtained using high-speed adaptive optics (AO) fundus cameras. Visible structures were analyzed for density using custom software. Additional retinal images were obtained using spectral domain optical coherence tomography (SD-OCT), and the four layers of the photoreceptor-retinal pigment epithelium complex (ELM, IS/OS, RPE1, RPE2) were evaluated. Cone photoreceptor length and the thickness of intraretinal layers were measured and compared to previously published normative data. Results. The adult male subject had infantile onset nystagmus while the three other patients did not. In the adult male patient, a normal appearing cone mosaic was observed. However, the three other subjects had a sparse mosaic of cones remaining at the fovea, with no structure visible outside the central fovea. On SD-OCT, the adult male subject had a very shallow foveal pit, with all major retinal layers being visible, and both inner segment (IS) and outer segment (OS) length were within normal limits. In the other three patients, while all four layers were visible in the central fovea and IS length was within normal limits, the OS length was significantly decreased. Peripherally the IS/OS layer decreased in intensity, and the RPE1 layer was no longer discernable, in keeping with the lack of cone

Vestibulo-cortical Hemispheric Dominance: the link between Anxiety and the Vestibular System?

PubMed

Bednarczuk, Nadja F; Casanovas Ortega, Marta; Fluri, Anne-Sophie; Arshad, Qadeer

2018-05-16

Vestibular processing and anxiety networks are functionally intertwined, as demonstrated by reports of reciprocal influences upon each other. Yet whether there is an underlying link between these two systems remains unknown Previous findings have highlighted the involvement of hemispheric lateralisation in processing of both anxiety and vestibular signals. Accordingly, we explored the interaction between vestibular cortical processing and anxiety by assessing the relationship between anxiety levels and the degree of hemispheric lateralisation of vestibulo-cortical processing in 64 right-handed, healthy individuals. Vestibulo-cortical hemispheric lateralisation was determined by gaging the degree of caloric-induced nystagmus suppression following modulation of cortical excitability using trans-cranial direct current stimulation targeted over the posterior parietal cortex, an area implicated in the processing of vestibular signals. The degree of nystagmus suppression yields an objective biomarker, allowing the quantification of the degree of right vestibulo-cortical hemisphere dominance. Anxiety levels were quantified using the Trait component of the Spielberger State-Trait Anxiety Questionnaire. Our findings demonstrate that the degree of an individual's vestibulo-cortical hemispheric dominance correlates with their anxiety levels. That is, those individuals with greater right hemispheric vestibulo-cortical dominance exhibited lower levels of anxiety. By extension, our results support the notion that hemispheric lateralisation determines an individual's emotional processing, thereby linking cortical circuits involved in processing anxiety and vestibular signals respectively. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Molecular and clinical studies of X-linked deafness among Pakistani families.

PubMed

Waryah, Ali M; Ahmed, Zubair M; Bhinder, Munir A; Binder, Munir A; Choo, Daniel I; Sisk, Robert A; Shahzad, Mohsin; Khan, Shaheen N; Friedman, Thomas B; Riazuddin, Sheikh; Riazuddin, Saima

2011-07-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132 and PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild-to-profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling and molecular epidemiology of hearing loss among Pakistanis.

Molecular and Clinical Studies of X-linked Deafness Among Pakistani Families

PubMed Central

Waryah, Ali M.; Ahmed, Zubair M.; Choo, Daniel I.; Sisk, Robert A.; Binder, Munir A.; Shahzad, Mohsin; Khan, Shaheen N.; Friedman, Thomas B.; Riazuddin, Sheikh; Riazuddin, Saima

2011-01-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132, PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild to profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling, and molecular epidemiology of hearing loss among Pakistanis. PMID:21633365

The retinal rod Na(+)/Ca(2+),K(+) exchanger contains a noncleaved signal sequence required for translocation of the N terminus.

PubMed

McKiernan, C J; Friedlander, M

1999-12-31

The retinal rod Na(+)/Ca(2+),K(+) exchanger (RodX) is a polytopic membrane protein found in photoreceptor outer segments where it is the principal extruder of Ca(2+) ions during light adaptation. We have examined the role of the N-terminal 65 amino acids in targeting, translocation, and integration of the RodX using an in vitro translation/translocation system. cDNAs encoding human RodX and bovine RodX through the first transmembrane domain were correctly targeted and integrated into microsomal membranes; deletion of the N-terminal 65 amino acids (aa) resulted in a translation product that was not targeted or integrated. Deletion of the first 65 aa had no effect on membrane targeting of full-length RodX, but the N-terminal hydrophilic domain no longer translocated. Chimeric constructs encoding the first 65 aa of bovine RodX fused to globin were translocated across microsomal membranes, demonstrating that the sequence could function heterologously. Studies of fresh bovine retinal extracts demonstrated that the first 65 aa are present in the native protein. These data demonstrate that the first 65 aa of RodX constitute an uncleaved signal sequence required for the efficient membrane targeting and proper membrane integration of RodX.

Samd7 is a cell type-specific PRC1 component essential for establishing retinal rod photoreceptor identity

PubMed Central

Omori, Yoshihiro; Kubo, Shun; Kon, Tetsuo; Furuhashi, Mayu; Narita, Hirotaka; Kominami, Taro; Ueno, Akiko; Tsutsumi, Ryotaro; Chaya, Taro; Yamamoto, Haruka; Suetake, Isao; Ueno, Shinji; Koseki, Haruhiko; Furukawa, Takahisa

2017-01-01

Precise transcriptional regulation controlled by a transcription factor network is known to be crucial for establishing correct neuronal cell identities and functions in the CNS. In the retina, the expression of various cone and rod photoreceptor cell genes is regulated by multiple transcription factors; however, the role of epigenetic regulation in photoreceptor cell gene expression has been poorly understood. Here, we found that Samd7, a rod-enriched sterile alpha domain (SAM) domain protein, is essential for silencing nonrod gene expression through H3K27me3 regulation in rod photoreceptor cells. Samd7-null mutant mice showed ectopic expression of nonrod genes including S-opsin in rod photoreceptor cells and rod photoreceptor cell dysfunction. Samd7 physically interacts with Polyhomeotic homologs (Phc proteins), components of the Polycomb repressive complex 1 (PRC1), and colocalizes with Phc2 and Ring1B in Polycomb bodies. ChIP assays showed a significant decrease of H3K27me3 in the genes up-regulated in the Samd7-deficient retina, showing that Samd7 deficiency causes the derepression of nonrod gene expression in rod photoreceptor cells. The current study suggests that Samd7 is a cell type-specific PRC1 component epigenetically defining rod photoreceptor cell identity. PMID:28900001

Samd7 is a cell type-specific PRC1 component essential for establishing retinal rod photoreceptor identity.

PubMed

Omori, Yoshihiro; Kubo, Shun; Kon, Tetsuo; Furuhashi, Mayu; Narita, Hirotaka; Kominami, Taro; Ueno, Akiko; Tsutsumi, Ryotaro; Chaya, Taro; Yamamoto, Haruka; Suetake, Isao; Ueno, Shinji; Koseki, Haruhiko; Nakagawa, Atsushi; Furukawa, Takahisa

2017-09-26

Precise transcriptional regulation controlled by a transcription factor network is known to be crucial for establishing correct neuronal cell identities and functions in the CNS. In the retina, the expression of various cone and rod photoreceptor cell genes is regulated by multiple transcription factors; however, the role of epigenetic regulation in photoreceptor cell gene expression has been poorly understood. Here, we found that Samd7, a rod-enriched sterile alpha domain (SAM) domain protein, is essential for silencing nonrod gene expression through H3K27me3 regulation in rod photoreceptor cells. Samd7- null mutant mice showed ectopic expression of nonrod genes including S-opsin in rod photoreceptor cells and rod photoreceptor cell dysfunction. Samd7 physically interacts with Polyhomeotic homologs (Phc proteins), components of the Polycomb repressive complex 1 (PRC1), and colocalizes with Phc2 and Ring1B in Polycomb bodies. ChIP assays showed a significant decrease of H3K27me3 in the genes up-regulated in the Samd7 -deficient retina, showing that Samd7 deficiency causes the derepression of nonrod gene expression in rod photoreceptor cells. The current study suggests that Samd7 is a cell type-specific PRC1 component epigenetically defining rod photoreceptor cell identity.

X linked mental retardation: a clinical guide.

PubMed

Raymond, F L

2006-03-01

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.

Alouatta trichromatic color vision: cone spectra and physiological responses studied with microspectrophotometry and single unit retinal electrophysiology.

PubMed

Silveira, Luiz Carlos L; Saito, Cézar A; da Silva Filho, Manoel; Kremers, Jan; Bowmaker, James K; Lee, Barry B

2014-01-01

The howler monkeys (Alouatta sp.) are the only New World primates to exhibit routine trichromacy. Both males and females have three cone photopigments. However, in contrast to Old World monkeys, Alouatta has a locus control region upstream of each opsin gene on the X-chromosome and this might influence the retinal organization underlying its color vision. Post-mortem microspectrophotometry (MSP) was performed on the retinae of two male Alouatta to obtain rod and cone spectral sensitivities. The MSP data were consistent with only a single opsin being expressed in each cone and electrophysiological data were consistent with this primate expressing full trichromacy. To study the physiological organization of the retina underlying Alouatta trichromacy, we recorded from retinal ganglion cells of the same animals used for MSP measurements with a variety of achromatic and chromatic stimulus protocols. We found MC cells and PC cells in the Alouatta retina with similar properties to those previously found in the retina of other trichromatic primates. MC cells showed strong phasic responses to luminance changes and little response to chromatic pulses. PC cells showed strong tonic response to chromatic changes and small tonic response to luminance changes. Responses to other stimulus protocols (flicker photometry; changing the relative phase of red and green modulated lights; temporal modulation transfer functions) were also similar to those recorded in other trichromatic primates. MC cells also showed a pronounced frequency double response to chromatic modulation, and with luminance modulation response saturation accompanied by a phase advance between 10-20 Hz, characteristic of a contrast gain mechanism. This indicates a very similar retinal organization to Old-World monkeys. Cone-specific opsin expression in the presence of a locus control region for each opsin may call into question the hypothesis that this region exclusively controls opsin expression.

A Simulation of X-Linked Inheritance.

ERIC Educational Resources Information Center

Harrell, Pamela Esprivalo

1997-01-01

Describes how to lead students through a classroom-based simulation to teach a variety of concepts such as X-linked traits, sex determination, and sex anomalies. The simulation utilizes inexpensive materials such as plastic eggs that twist apart to represent human eggs and sperm. (AIM)

The dual rod system of amphibians supports colour discrimination at the absolute visual threshold

PubMed Central

Yovanovich, Carola A. M.; Koskela, Sanna M.; Nevala, Noora; Kondrashev, Sergei L.

2017-01-01

The presence of two spectrally different kinds of rod photoreceptors in amphibians has been hypothesized to enable purely rod-based colour vision at very low light levels. The hypothesis has never been properly tested, so we performed three behavioural experiments at different light intensities with toads (Bufo) and frogs (Rana) to determine the thresholds for colour discrimination. The thresholds of toads were different in mate choice and prey-catching tasks, suggesting that the differential sensitivities of different spectral cone types as well as task-specific factors set limits for the use of colour in these behavioural contexts. In neither task was there any indication of rod-based colour discrimination. By contrast, frogs performing phototactic jumping were able to distinguish blue from green light down to the absolute visual threshold, where vision relies only on rod signals. The remarkable sensitivity of this mechanism comparing signals from the two spectrally different rod types approaches theoretical limits set by photon fluctuations and intrinsic noise. Together, the results indicate that different pathways are involved in processing colour cues depending on the ecological relevance of this information for each task. This article is part of the themed issue ‘Vision in dim light’. PMID:28193811

Dominantly inherited syndrome of microcephaly and cleft palate.

PubMed

Halal, F

1983-05-01

Two sisters and their mother had a syndrome of microcephaly, cleft palate, and variable anomalies such as unusual facial appearance, hypotelorism, abnormal retinal pigmentation, maxillary hypoplasia, goiter, camptodactyly, mild mental retardation, and abnormal dermatoglyphics. This is an evidently dominantly inherited trait, either autosomal or X-linked.

Escape of X-linked miRNA genes from meiotic sex chromosome inactivation

PubMed Central

Sosa, Enrique; Flores, Luis; Yan, Wei; McCarrey, John R.

2015-01-01

Past studies have indicated that transcription of all X-linked genes is repressed by meiotic sex chromosome inactivation (MSCI) during the meiotic phase of spermatogenesis in mammals. However, more recent studies have shown an increase in steady-state levels of certain X-linked miRNAs in pachytene spermatocytes, suggesting that either synthesis of these miRNAs increases or that degradation of these miRNAs decreases dramatically in these cells. To distinguish between these possibilities, we performed RNA-FISH to detect nascent transcripts from multiple miRNA genes in various spermatogenic cell types. Our results show definitively that Type I X-linked miRNA genes are subject to MSCI, as are all or most X-linked mRNA genes, whereas Type II and III X-linked miRNA genes escape MSCI by continuing ongoing, active transcription in primary spermatocytes. We corroborated these results by co-localization of RNA-FISH signals with both a corresponding DNA-FISH signal and an immunofluorescence signal for RNA polymerase II. We also found that X-linked miRNA genes that escape MSCI locate non-randomly to the periphery of the XY body, whereas genes that are subject to MSCI remain located within the XY body in pachytene spermatocytes, suggesting that the mechanism of escape of X-linked miRNA genes from MSCI involves their relocation to a position outside of the repressive chromatin domain associated with the XY body. The fact that Type II and III X-linked miRNA genes escape MSCI suggests an immediacy of function of the encoded miRNAs specifically required during the meiotic stages of spermatogenesis. PMID:26395485

Data consistency-driven scatter kernel optimization for x-ray cone-beam CT

NASA Astrophysics Data System (ADS)

Kim, Changhwan; Park, Miran; Sung, Younghun; Lee, Jaehak; Choi, Jiyoung; Cho, Seungryong

2015-08-01

Accurate and efficient scatter correction is essential for acquisition of high-quality x-ray cone-beam CT (CBCT) images for various applications. This study was conducted to demonstrate the feasibility of using the data consistency condition (DCC) as a criterion for scatter kernel optimization in scatter deconvolution methods in CBCT. As in CBCT, data consistency in the mid-plane is primarily challenged by scatter, we utilized data consistency to confirm the degree of scatter correction and to steer the update in iterative kernel optimization. By means of the parallel-beam DCC via fan-parallel rebinning, we iteratively optimized the scatter kernel parameters, using a particle swarm optimization algorithm for its computational efficiency and excellent convergence. The proposed method was validated by a simulation study using the XCAT numerical phantom and also by experimental studies using the ACS head phantom and the pelvic part of the Rando phantom. The results showed that the proposed method can effectively improve the accuracy of deconvolution-based scatter correction. Quantitative assessments of image quality parameters such as contrast and structure similarity (SSIM) revealed that the optimally selected scatter kernel improves the contrast of scatter-free images by up to 99.5%, 94.4%, and 84.4%, and of the SSIM in an XCAT study, an ACS head phantom study, and a pelvis phantom study by up to 96.7%, 90.5%, and 87.8%, respectively. The proposed method can achieve accurate and efficient scatter correction from a single cone-beam scan without need of any auxiliary hardware or additional experimentation.

An Assessment of the Suitability of Cone Penetration Testing in Identifying the Late Quaternary Successions Formed in Tide-dominated Tnvironments: A Case Study from the Eastern China Coastal Plain

NASA Astrophysics Data System (ADS)

Zhang, X.; Lin, C. M., Sr.; Dalrymple, R. W.; Gao, S., Sr.

2017-12-01

Cone penetration testing (CPT) has proved to be as an effective method for sedimentological purposes in wave-dominated coastal environments. This study, based upon interpretation of 500 CPTs, carried out in the late Quaternary Qiantang River incised-valley fill over the eastern China coastal plain, shows how CPTs can also be used for detailed facies characterization and identification of the key surfaces for sequence-stratigraphic interpretation in tide-dominated systems based upon estimation of three major parameters: cone-tip resistance (qc), sleeve friction (fs), and the ratio of fs and qc (FR). Plotting of qc versus FR, in combination with the CPT curve shape and the relative depth in profile, is adopted as the major tool. The lithologic character which is controlled mainly by sediment supply and dynamics, and post-depositional diagenesis is respected as the main factor affecting how well the CPT technique works. Within this particular tide-dominated environment, dominated by non-cohesive sand and silt, the accumulation of the materials from fluid muds is rare. As a result, the tidal-channel deposits exhibit the nature of coarse-grained deposits, different from that of the other mud-dominated facies associations. On the other hand, a distinct layer of fine-grained deposit at the base of the Holocene sequences was subjected to early diagenesis during the last glacial maximum and early transgression, to become uniformly hard and over-consolidated, geotechnically distinct from the overlying softer sediments. Besides, due to the different sediment dynamics, the tidal-flat and salt-marsh deposits exhibit a distinct geotechnical behavior with the offshore shallow marine muddy deposits. All the above mentioned situations provide the basis for the recognition of facies association and the correlated key surfaces, even for the mapping of the incised-valley boundary. As a consequence, the CPT method has a potential to be a very attractive alternative to economically less

In Vivo Imaging of Human Cone Photoreceptor Inner Segments

PubMed Central

Scoles, Drew; Sulai, Yusufu N.; Langlo, Christopher S.; Fishman, Gerald A.; Curcio, Christine A.; Carroll, Joseph; Dubra, Alfredo

2014-01-01

Purpose. An often overlooked prerequisite to cone photoreceptor gene therapy development is residual photoreceptor structure that can be rescued. While advances in adaptive optics (AO) retinal imaging have recently enabled direct visualization of individual cone and rod photoreceptors in the living human retina, these techniques largely detect strongly directionally-backscattered (waveguided) light from normal intact photoreceptors. This represents a major limitation in using existing AO imaging to quantify structure of remnant cones in degenerating retina. Methods. Photoreceptor inner segment structure was assessed with a novel AO scanning light ophthalmoscopy (AOSLO) differential phase technique, that we termed nonconfocal split-detector, in two healthy subjects and four subjects with achromatopsia. Ex vivo preparations of five healthy donor eyes were analyzed for comparison of inner segment diameter to that measured in vivo with split-detector AOSLO. Results. Nonconfocal split-detector AOSLO reveals the photoreceptor inner segment with or without the presence of a waveguiding outer segment. The diameter of inner segments measured in vivo is in good agreement with histology. A substantial number of foveal and parafoveal cone photoreceptors with apparently intact inner segments were identified in patients with the inherited disease achromatopsia. Conclusions. The application of nonconfocal split-detector to emerging human gene therapy trials will improve the potential of therapeutic success, by identifying patients with sufficient retained photoreceptor structure to benefit the most from intervention. Additionally, split-detector imaging may be useful for studies of other retinal degenerations such as AMD, retinitis pigmentosa, and choroideremia where the outer segment is lost before the remainder of the photoreceptor cell. PMID:24906859

Facile Synthesis of Rod-like Cu2-x Se and Insight into its Improved Lithium-Storage Property.

PubMed

Li, He; Jiang, Jiali; Wang, Feng; Huang, Jianxing; Wang, Yunhui; Zhang, Yiyong; Zhao, Jinbao

2017-05-22

A rod-like Cu 2-x Se is synthesized by a facile water evaporation process. The electrochemical reaction mechanism is investigated by ex situ X-ray diffraction (XRD). By adopting an ether-based electrolyte instead of a carbonate-based electrolyte, the electrochemical performance of Cu 2-x Se electrodes improved significantly. The Cu 2-x Se electrodes exhibit outstanding cycle performance: after 1000 cycles, 160 mA h g -1 can be maintained with a retention of 80.3 %. At current densities of 100, 200, 500, and 1000 mA g -1 , the capacity of a Cu 2-x Se/Li battery was 208, 202, 200, and 198 mA h g -1 , respectively, showing excellent rate capability. The 4-probe conductivity measurements along with electrochemical impendence spectroscopy (EIS) and cyclic voltammetry (CV) tests illustrate that the Cu 2-x Se electrodes display high specific conductivity and impressive lithium-ion diffusion rate, which makes the Cu 2-x Se a promising anode material for lithium-ion batteries. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Noise reduction in a Mach 5 wind tunnel with a rectangular rod-wall sound shield

NASA Technical Reports Server (NTRS)

Creel, T. R., Jr.; Keyes, J. W.; Beckwith, I. E.

1980-01-01

A rod wall sound shield was tested over a range of Reynolds numbers of 0.5 x 10 to the 7th power to 8.0 x 10 to the 7th power per meter. The model consisted of a rectangular array of longitudinal rods with boundary-layer suction through gaps between the rods. Suitable measurement techniques were used to determine properties of the flow and acoustic disturbance in the shield and transition in the rod boundary layers. Measurements indicated that for a Reynolds number of 1.5 x 10 to the 9th power the noise in the shielded region was significantly reduced, but only when the flow is mostly laminar on the rods. Actual nozzle input noise measured on the nozzle centerline before reflection at the shield walls was attenuated only slightly even when the rod boundary layer were laminar. At a lower Reynolds number, nozzle input noise at noise levels in the shield were still too high for application to a quiet tunnel. At Reynolds numbers above 2.0 x 10 the the 7th power per meter, measured noise levels were generally higher than nozzle input levels, probably due to transition in the rod boundary layers. The small attenuation of nozzle input noise at intermediate Reynolds numbers for laminar rod layers at the acoustic origins is apparently due to high frequencies of noise.

Development of a full ice-cream cone model for halo CME structures

NASA Astrophysics Data System (ADS)

Na, Hyeonock; Moon, Yong-Jae

2015-04-01

The determination of three dimensional parameters (e.g., radial speed, angular width, source location) of Coronal Mass Ejections (CMEs) is very important for space weather forecast. To estimate these parameters, several cone models based on a flat cone or a shallow ice-cream cone with spherical front have been suggested. In this study, we investigate which cone model is proper for halo CME morphology using 33 CMEs which are identified as halo CMEs by one spacecraft (SOHO or STEREO-A or B) and as limb CMEs by the other ones. From geometrical parameters of these CMEs such as their front curvature, we find that near full ice-cream cone CMEs (28 events) are dominant over shallow ice-cream cone CMEs (5 events). So we develop a new full ice-cream cone model by assuming that a full ice-cream cone consists of many flat cones with different heights and angular widths. This model is carried out by the following steps: (1) construct a cone for given height and angular width, (2) project the cone onto the sky plane, (3) select points comprising the outer boundary, (4) minimize the difference between the estimated projection points with the observed ones. We apply this model to several halo CMEs and compare the results with those from other methods such as a Graduated Cylindrical Shell model and a geometrical triangulation method.

A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy.

PubMed

Chen, Z Y; Battinelli, E M; Fielder, A; Bundey, S; Sims, K; Breakefield, X O; Craig, I W

1993-10-01

Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder characterized by an abnormality of the peripheral retina. Both autosomal dominant (adFEVR) and X-linked (XLFEVR) forms have been described, but the biochemical defect(s) underlying the symptoms are unknown. Molecular analysis of the Norrie gene locus (NDP) in a four generation FEVR family (shown previously to exhibit linkage to the X-chromosome markers DXS228 and MAOA (Xp11.4-p11.3)) reveals a missense mutation in the highly conserved region of the NDP gene, which caused a neutral amino acid substitution (Leu124Phe), was detected in all of the affected males, but not in the unaffected family members, nor in normal controls. The observations suggest that phenotypes of both XLFEVR and Norrie disease can result from mutations in the same gene.

Die Fledermaus: Regarding Optokinetic Contrast Sensitivity and Light-Adaptation, Chicks Are Mice with Wings

PubMed Central

Shi, Qing; Stell, William K.

2013-01-01

Background Through adaptation, animals can function visually under an extremely broad range of light intensities. Light adaptation starts in the retina, through shifts in photoreceptor sensitivity and kinetics plus modulation of visual processing in retinal circuits. Although considerable research has been conducted on retinal adaptation in nocturnal species with rod-dominated retinas, such as the mouse, little is known about how cone-dominated avian retinas adapt to changes in mean light intensity. Methodology/Principal Findings We used the optokinetic response to characterize contrast sensitivity (CS) in the chick retina as a function of spatial frequency and temporal frequency at different mean light intensities. We found that: 1) daytime, cone-driven CS was tuned to spatial frequency; 2) nighttime, presumably rod-driven CS was tuned to temporal frequency and spatial frequency; 3) daytime, presumably cone-driven CS at threshold intensity was invariant with temporal and spatial frequency; and 4) daytime photopic CS was invariant with clock time. Conclusion/Significance Light- and dark-adaptational changes in CS were investigated comprehensively for the first time in the cone-dominated retina of an avian, diurnal species. The chick retina, like the mouse retina, adapts by using a “day/night” or “cone/rod” switch in tuning preference during changes in lighting conditions. The chick optokinetic response is an attractive model for noninvasive, behavioral studies of adaptation in retinal circuitry in health and disease. PMID:24098693

Domain requirements for the Dock adapter protein in growth- cone signaling

PubMed Central

Rao, Yong; Zipursky, S. Lawrence

1998-01-01

Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly specialized for growth-cone guidance. In this paper, we demonstrate that Dock can couple signals in either an SH2-dependent or an SH2-independent fashion in photoreceptor (R cell) growth cones, and that Dock displays different domain requirements in different neurons. PMID:9482841

Domain requirements for the Dock adapter protein in growth- cone signaling.

PubMed

Rao, Y; Zipursky, S L

1998-03-03

Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly specialized for growth-cone guidance. In this paper, we demonstrate that Dock can couple signals in either an SH2-dependent or an SH2-independent fashion in photoreceptor (R cell) growth cones, and that Dock displays different domain requirements in different neurons.

Craniofacioskeletal Syndrome: An X-Linked Dominant Disorder With Early Lethality in Males

PubMed Central

Stevenson, Roger E.; Brasington, Cam K.; Skinner, Cindy; Simensen, Richard J.; Spence, J. Edward; Kesler, Shelli; Reiss, Allan L.; Schwartz, Charles E.

2011-01-01

A syndrome with multisystem manifestations has been observed in three generations of a Caucasian family. The findings in seven females provide a composite clinical picture of microcephaly, short stature, small retroverted ears, full tip of the nose overhanging the columella, short philtrum, thin upper lip, soft tissue excrescences at the angle of the mouth, small mandible, small hands and feet with brachydactyly, finger V clinodactyly, flat feet, an excessive number of fingerprint arches, and mild impairment of cognitive function. Two males were more severely affected and died in the initial months of life. They showed intrauterine growth retardation, broad cranium with wide sutures and fontanelles, cardiac defects, small hands and feet with abnormal digital creases and small nails, and genital abnormalities. The affected males had low serum calcium in the neonatal period. Serum calcium, phosphorous, and parathormone levels in the females were normal. Radiographs showed cortical thickening of the long bones, underdevelopment of the frontal sinuses, narrow pelvis and hypoplasia of the middle phalanx of finger five. MRI of the brain showed slightly reduced brain volumes and an extra gyrus of the superior temporal region. X-inactivation studies showed near complete skewing in two affected females, but were not informative in three others. X-linkage as the mode of inheritance is proposed on the basis of different severity in males/females, complete skewing of X-inactivation in informative females, and a lod score (1.5) suggestive of linkage to markers in Xq26-q27. PMID:17853486

Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia

PubMed Central

Kohl, Susanne; Zobor, Ditta; Chiang, Wei-Chieh; Weisschuh, Nicole; Staller, Jennifer; Menendez, Irene Gonzalez; Chang, Stanley; Beck, Susanne C; Garrido, Marina Garcia; Sothilingam, Vithiyanjali; Seeliger, Mathias W; Stanzial, Franco; Benedicenti, Francesco; Inzana, Francesca; Héon, Elise; Vincent, Ajoy; Beis, Jill; Strom, Tim M; Rudolph, Günther; Roosing, Susanne; den Hollander, Anneke I; Cremers, Frans P M; Lopez, Irma; Ren, Huanan; Moore, Anthony T; Webster, Andrew R; Michaelides, Michel; Koenekoop, Robert K; Zrenner, Eberhart; Kaufman, Randal J; Tsang, Stephen H; Wissinger, Bernd; Lin, Jonathan H

2015-01-01

Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6−/− mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype. PMID:26029869

Twin robotic x-ray system for 2D radiographic and 3D cone-beam CT imaging

NASA Astrophysics Data System (ADS)

Fieselmann, Andreas; Steinbrener, Jan; Jerebko, Anna K.; Voigt, Johannes M.; Scholz, Rosemarie; Ritschl, Ludwig; Mertelmeier, Thomas

2016-03-01

In this work, we provide an initial characterization of a novel twin robotic X-ray system. This system is equipped with two motor-driven telescopic arms carrying X-ray tube and flat-panel detector, respectively. 2D radiographs and fluoroscopic image sequences can be obtained from different viewing angles. Projection data for 3D cone-beam CT reconstruction can be acquired during simultaneous movement of the arms along dedicated scanning trajectories. We provide an initial evaluation of the 3D image quality based on phantom scans and clinical images. Furthermore, initial evaluation of patient dose is conducted. The results show that the system delivers high image quality for a range of medical applications. In particular, high spatial resolution enables adequate visualization of bone structures. This system allows 3D X-ray scanning of patients in standing and weight-bearing position. It could enable new 2D/3D imaging workflows in musculoskeletal imaging and improve diagnosis of musculoskeletal disorders.

Morphological Diversity of the Rod Spherule: A Study of Serially Reconstructed Electron Micrographs

PubMed Central

Li, Shuai; Mitchell, Joe; Briggs, Deidrie J.; Young, Jaime K.; Long, Samuel S.; Fuerst, Peter G.

2016-01-01

Purpose Rod spherules are the site of the first synaptic contact in the retina’s rod pathway, linking rods to horizontal and bipolar cells. Rod spherules have been described and characterized through electron micrograph (EM) and other studies, but their morphological diversity related to retinal circuitry and their intracellular structures have not been quantified. Most rod spherules are connected to their soma by an axon, but spherules of rods on the surface of the Mus musculus outer plexiform layer often lack an axon and have a spherule structure that is morphologically distinct from rod spherules connected to their soma by an axon. Retraction of the rod axon and spherule is often observed in disease processes and aging, and the retracted rod spherule superficially resembles rod spherules lacking an axon. We hypothesized that retracted spherules take on an axonless spherule morphology, which may be easier to maintain in a diseased state. To test our hypothesis, we quantified the spatial organization and subcellular structures of rod spherules with and without axons. We then compared them to the retracted spherules in a disease model, mice that overexpress Dscam (Down syndrome cell adhesion molecule), to gain a better understanding of the rod synapse in health and disease. Methods We reconstructed serial EM images of wild type and DscamGoF (gain of function) rod spherules at a resolution of 7 nm in the X-Y axis and 60 nm in the Z axis. Rod spherules with and without axons, and retracted spherules in the DscamGoF retina, were reconstructed. The rod spherule intracellular organelles, the invaginating dendrites of rod bipolar cells and horizontal cell axon tips were also reconstructed for statistical analysis. Results Stereotypical rod (R1) spherules occupy the outer two-thirds of the outer plexiform layer (OPL), where they present as spherical terminals with large mitochondria. This spherule group is highly uniform and composed more than 90% of the rod spherule

Morphological Diversity of the Rod Spherule: A Study of Serially Reconstructed Electron Micrographs.

PubMed

Li, Shuai; Mitchell, Joe; Briggs, Deidrie J; Young, Jaime K; Long, Samuel S; Fuerst, Peter G

2016-01-01

Rod spherules are the site of the first synaptic contact in the retina's rod pathway, linking rods to horizontal and bipolar cells. Rod spherules have been described and characterized through electron micrograph (EM) and other studies, but their morphological diversity related to retinal circuitry and their intracellular structures have not been quantified. Most rod spherules are connected to their soma by an axon, but spherules of rods on the surface of the Mus musculus outer plexiform layer often lack an axon and have a spherule structure that is morphologically distinct from rod spherules connected to their soma by an axon. Retraction of the rod axon and spherule is often observed in disease processes and aging, and the retracted rod spherule superficially resembles rod spherules lacking an axon. We hypothesized that retracted spherules take on an axonless spherule morphology, which may be easier to maintain in a diseased state. To test our hypothesis, we quantified the spatial organization and subcellular structures of rod spherules with and without axons. We then compared them to the retracted spherules in a disease model, mice that overexpress Dscam (Down syndrome cell adhesion molecule), to gain a better understanding of the rod synapse in health and disease. We reconstructed serial EM images of wild type and DscamGoF (gain of function) rod spherules at a resolution of 7 nm in the X-Y axis and 60 nm in the Z axis. Rod spherules with and without axons, and retracted spherules in the DscamGoF retina, were reconstructed. The rod spherule intracellular organelles, the invaginating dendrites of rod bipolar cells and horizontal cell axon tips were also reconstructed for statistical analysis. Stereotypical rod (R1) spherules occupy the outer two-thirds of the outer plexiform layer (OPL), where they present as spherical terminals with large mitochondria. This spherule group is highly uniform and composed more than 90% of the rod spherule population. Rod spherules

Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease.

PubMed

Horn, Morten A; Erichsen, Martina M; Wolff, Anette S B; Månsson, Jan-Eric; Husebye, Eystein S; Tallaksen, Chantal M E; Skjeldal, Ola H

2013-09-01

X-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. Among 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X-linked adrenoleukodystrophy in men. Eighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X-linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X-linked adrenoleukodystrophy constitute 1·5% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. We found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids. © 2013 John Wiley & Sons Ltd.

MULTIMODAL IMAGING OF MOSAIC RETINOPATHY IN CARRIERS OF HEREDITARY X-LINKED RECESSIVE DISEASES.

PubMed

Wu, An-Lun; Wang, Jung-Pan; Tseng, Yun-Ju; Liu, Laura; Kang, Yu-Chuan; Chen, Kuan-Jen; Chao, An-Ning; Yeh, Lung-Kun; Chen, Tun-Lu; Hwang, Yih-Shiou; Wu, Wei-Chi; Lai, Chi-Chun; Wang, Nan-Kai

2018-05-01

To investigate the clinical features in carriers of X-linked retinitis pigmentosa, X-linked ocular albinism, and choroideremia (CHM) using multimodal imaging and to assess their diagnostic value in these three mosaic retinopathies. We prospectively examined 14 carriers of 3 X-linked recessive disorders (X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM). Details of abnormalities of retinal morphology were evaluated using fundus photography, fundus autofluorescence (FAF) imaging, and spectral domain optical coherence tomography. In six X-linked retinitis pigmentosa carriers, fundus appearance varied from unremarkable to the presence of tapetal-like reflex and pigmentary changes. On FAF imaging, all carriers exhibited a bright radial reflex against a dark background. By spectral domain optical coherence tomography, loss of the ellipsoid zone in the macula was observed in 3 carriers (50%). Regarding the retinal laminar architecture, 4 carriers (66.7%) showed thinning of the outer nuclear layer and a dentate appearance of the outer plexiform layer. All five X-linked ocular albinism carriers showed a characteristic mud-splatter patterned fundus, dark radial streaks against a bright background on FAF imaging, and a normal-appearing retinal structure by spectral domain optical coherence tomography imaging. Two of the 3 CHM carriers (66.7%) showed a diffuse moth-eaten appearance of the fundus, and all 3 showed irregular hyper-FAF and hypo-FAF spots throughout the affected area. In the CHM carriers, the structural changes observed by spectral domain optical coherence tomography imaging were variable. Our findings in an Asian cohort suggest that FAF imaging is a practical diagnostic test for differentiating X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM carriers. Wide-field FAF is an easy and helpful adjunct to testing for the correct diagnosis and identification of lyonization in carriers of these three mosaic retinopathies.

Mechanisms that limit the light stimulus frequency following through the APB sensitive and insensitive rod Off-pathways

PubMed Central

Bai, Xia; Zhu, Junling; Yang, Jinnan; Savoie, Brian T.; Wang, Guo-Yong

2009-01-01

In the retina, rod signal pathways process scotopic visual information. Light decrements are mediated by two distinct groups of rod pathways in the dark adapted retina that can be differentiated on the basis of their sensitivity to the glutamate agonist DL-2-amino-4-phosphonobutyric acid (APB). We have found that the APB sensitive and insensitive rod Off-pathways signal different light decrement information: the APB sensitive rod Off-pathway conveys slow and low frequency light signals, whereas the APB insensitive rod Off-pathways mediate fast and high frequency light signals (Wang, 2006). However, the mechanisms which limit the frequency following through the APB sensitive and insensitive rod Off-pathways remain unknown. In the current study, whole-cell patch-clamp recordings were made from ganglion cells in dark and light adapted mouse retina to identify the mechanisms that limit the frequency following through the APB sensitive and insensitive rod Off-pathways. The results showed that the sites from AII amacrine cells to Off cone bipolar cells are the major mechanisms that limit the frequency following through the APB sensitive rod Off-pathway. In the APB insensitive rod Off-pathways, rods themselves limited the frequency following through these pathways. Moreover, ganglion cells were able to follow higher frequencies under photopic conditions than under scotopic conditions. The Off responses followed lower frequencies than On responses under photopic conditions. This finding was observed in cells that yielded On or Off responses only as well as in On-Off cells. PMID:19406212

Genetics Home Reference: X-linked lymphoproliferative disease

MedlinePlus

... infects most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, ... severe susceptibility to EBV infection severe susceptibility to infectious mononucleosis X-linked lymphoproliferative syndrome XLP Related Information How ...

THE NuSTAR X-RAY SPECTRUM OF HERCULES X-1: A RADIATION-DOMINATED RADIATIVE SHOCK

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolff, Michael T.; Wood, Kent S.; Becker, Peter A.

2016-11-10

We report on new spectral modeling of the accreting X-ray pulsar Hercules X-1. Our radiation-dominated radiative shock model is an implementation of the analytic work of Becker and Wolff on Comptonized accretion flows onto magnetic neutron stars. We obtain a good fit to the spin-phase-averaged 4–78 keV X-ray spectrum observed by the Nuclear Spectroscopic Telescope Array during a main-on phase of the Her X-1 35 day accretion disk precession period. This model allows us to estimate the accretion rate, the Comptonizing temperature of the radiating plasma, the radius of the magnetic polar cap, and the average scattering opacity parameters inmore » the accretion column. This is in contrast to previous phenomenological models that characterized the shape of the X-ray spectrum, but could not determine the physical parameters of the accretion flow. We describe the spectral fitting details and discuss the interpretation of the accretion flow physical parameters.« less

Human Blue Cone Opsin Regeneration Involves Secondary Retinal Binding with Analog Specificity.

PubMed

Srinivasan, Sundaramoorthy; Fernández-Sampedro, Miguel A; Morillo, Margarita; Ramon, Eva; Jiménez-Rosés, Mireia; Cordomí, Arnau; Garriga, Pere

2018-03-27

Human color vision is mediated by the red, green, and blue cone visual pigments. Cone opsins are G-protein-coupled receptors consisting of an opsin apoprotein covalently linked to the 11-cis-retinal chromophore. All visual pigments share a common evolutionary origin, and red and green cone opsins exhibit a higher homology, whereas blue cone opsin shows more resemblance to the dim light receptor rhodopsin. Here we show that chromophore regeneration in photoactivated blue cone opsin exhibits intermediate transient conformations and a secondary retinoid binding event with slower binding kinetics. We also detected a fine-tuning of the conformational change in the photoactivated blue cone opsin binding site that alters the retinal isomer binding specificity. Furthermore, the molecular models of active and inactive blue cone opsins show specific molecular interactions in the retinal binding site that are not present in other opsins. These findings highlight the differential conformational versatility of human cone opsin pigments in the chromophore regeneration process, particularly compared to rhodopsin, and point to relevant functional, unexpected roles other than spectral tuning for the cone visual pigments. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

SWCX Emission from the Helium Focusing Cone - Model to Data Comparison

NASA Technical Reports Server (NTRS)

Koutroumpa, D.; Collier, M. R.; Kuntz, K. D.; Lallement, R.; Snowden, Steven L.

2009-01-01

A model for heliospheric solar wind charge exchange (SWCX) X-ray emission is applied to a series of XMM-Newton observations of the interplanetary focusing cone of interstellar helium. The X-ray data are from three coupled observations of the South Ecliptic Pole (SEP, to observe the cone) and the Hubble Deep Field-North (HDFN. to monitor global variations of the SWCX emission due to variations in the solar wind) from the period 24 November to 15 December 2003. There is good qualitative agreement between the model predictions and thc data with the maximum SWCX flux observed at an ecliptic longitude of approx. 72deg, consistent with the central longitude of the He cone. We observe a total excess of 2.1 +/- 1.3 LU in the O VII line and 2.0 +/- 0.9 LU in the 0 VIII line. However. the SWCX emission model, which was adjusted for solar wind conditions appropriate for late 2003, predicts an excess from the He cone of only 0.5 LU and 0.2 LU, respectively, in the O VII and O VIII lines. We discuss thc model to data comparison and provide possible explanations for the discrepancies. We also qualitatively reexamine our SWCX nocicl predictions in the 1/4 keV band with data from the ROSAT All-Sky Survey towards the North and South Ecliptic Poles, when the He cone was probably first detected in soft X-rays.

Microcomputed tomography and shock microdeformation studies on shatter cones

NASA Astrophysics Data System (ADS)

Zaag, Patrice Tristan; Reimold, Wolf Uwe; Hipsley, Christy Anna

2016-08-01

One of the aspects of impact cratering that are still not fully understood is the formation of shatter cones and related fracturing phenomena. Yet, shatter cones have been applied as an impact-diagnostic criterion for decades without the role of shock waves and target rock defects in their formation having been elucidated ever. We have tested the application of the nondestructive microcomputed tomography (μCT) method to visualize the interior of shatter cones in order to possibly resolve links between fracture patterns and shatter cone surface features (striations and intervening "valleys"). Shatter-coned samples from different impact sites and in different lithologies were investigated for their μCT suitability, with a shatter cone in sandstone from the Serra da Cangalha impact structure (Brazil) remaining as the most promising candidate because of the fracture resolution achieved. To validate the obtained CT data, the scanned specimen was cut into three orthogonal sets of thin sections. Scans with 13 μm resolution were obtained. μCT scans and microscopic analysis unraveled an orientation of subplanar fractures and related fluid inclusion trails, and planar fracture (PF) orientations in the interior of shatter cones. Planar deformation features (PDF) were observed predominantly near the shatter cone surface. Previously undescribed varieties of feather features (FF), in the form of lamellae emanating from curviplanar and curved fractures, as well as an "arrowhead"-like FF development with microlamellae originating from both sides of a PF, were observed. The timing of shatter cone formation was investigated by establishing temporal relations to the generation of various shock microscopic effects. Shatter cones are, thus, generated post- or syn-formation of PF, FF, subplanar fractures, and PDF. The earliest possible time for shatter cone formation is during the late stage of the compressional phase, that is, shock wave passage, of an impact event.

Use of the Cone Penetration Testing (CPT) method to interpret late Quaternary tide-dominated successions: A case study from the eastern China coastal plain

NASA Astrophysics Data System (ADS)

Zhang, Xia; Lin, Chun-Ming; Dalrymple, Robert W.; Gao, Shu; Canas, Daniel T.

2018-06-01

We evaluate the applicability of cone penetration testing (CPT), calibrated using adjacent cores, as a tool for the sedimentological and stratigraphic examination of late Quaternary tide-dominated successions in the eastern China coastal plain. The results indicate that the sedimentary facies and sequence-stratigraphic surfaces can be readily distinguished using CPT profiles in the Qiantang River incised-valley system because of their distinctive mechanical behavior. The lithologic character of the various facies, which is controlled mainly by sediment supply, dynamic processes and post-depositional diagenesis, is the key factor affecting how well the CPT technique works. Within this particular macrotidal environment, which is dominated by non-cohesive sand and silt in the tidal channels, the accumulation of fluid mud is rare. Consequently, the tidal-channel deposits exhibit the geotechnical properties of coarse-grained sediments, and can be easily distinguished from the mud-dominated facies. However, in the nearby Changjiang delta system which is characterized by very high suspended-sediment concentrations and an abundance of fine-grained cohesive sediments, the presence of channel-bottom fluid muds makes it difficult to recognize channel deposits, because of the lack of a sharp lithologic contrast at their base. Consequently, the CPT method might not be as universally effective in tide-dominated systems as it appears to be in wave-dominated settings. Care is needed in the interpretation of the results from tide-dominated successions because of the widespread presence of fluid muds, the heterolithic nature of tidal deposits, the rheological similarity between adjacent facies, and the averaging of geotechnical properties between the alternating finer and coarser layers.

Kinematics of Cone-In-Cone Growth, with Implications for Timing and Formation Mechanism

NASA Astrophysics Data System (ADS)

Hooker, J. N.; Cartwright, J. A.

2015-12-01

Cone-in-cone is an enigmatic structure. Similar to many fibrous calcite veins, cone-in-cone is generally formed of calcite and present in bedding-parallel vein-like accumulations within fine-grained rocks. Unlike most fibrous veins, cone-in-cone contains conical inclusions of host-rock material, creating nested, parallel cones throughout. A long-debated aspect of cone-in-cone structures is whether the calcite precipitated with its conical form (primary cone-in-cone), or whether the cones formed afterwards (secondary cone-in-cone). Trace dolomite within a calcite cone-in-cone structure from the Cretaceous of Jordan supports the primary hypothesis. The host sediment is a siliceous mud containing abundant rhombohedral dolomite grains. Dolomite rhombohedra are also distributed throughout the cone-in-cone. The rhombohedra within the cones are randomly oriented yet locally have dolomite overgrowths having boundaries that are aligned with calcite fibers. Evidence that dolomite co-precipitated with calcite, and did not replace calcite, includes (i) preferential downward extension of dolomite overgrowths, in the presumed growth-direction of the cone-in-cone, and (ii) planar, vertical borders between dolomite crystals and calcite fibers. Because dolomite overgrows host-sediment rhombohedra and forms fibers within the cones, it follows that the host-sediment was included within the growing cone-in-cone as the calcite precipitated, and not afterward. The host-sediment was not injected into the cone-in-cone along fractures, as the secondary-origin hypothesis suggests. This finding implies that cone-in-cone in general does not form over multiple stages, and thus has greater potential to preserve the chemical signature of its original precipitation. Because cone-in-cone likely forms before complete lithification of the host, and because the calcite displaces the host material against gravity, this chemical signature can preserve information about early overpressures in fine

Apparent X-linked primary ciliary dyskinesia associated with retinitis pigmentosa and a hearing loss.

PubMed

Krawczyński, Maciej R; Dmeńska, Hanna; Witt, Michał

2004-01-01

Three brothers, one 10-year-old and a pair of 14-year-old dizygotic twins--expressed the classical, early-onset retinitis pigmentosa (RP) with typical ophthalmoscopic findings, night blindness, visual field constricted to 10 degrees and flat ERG response. All three brothers were also diagnosed with primary ciliary dyskinesia (PCD) and had recurrent respiratory infections, chronic sinusitis and bronchiectasis. In all of them, resection of the middle lobe of the right lung was performed. A similar clinical picture of coexisting RP and PCD was noted in the brother of the probands' mother. All probands displayed situs solitus. Consistent with the X-linked mode of RP inheritance, there were also three obligatory female carriers of the disorder in this family: the mother of the affected boys, her mother and a daughter of her brother. In all of them, retinitis pigmentosa "sine pigmento" was found with milder but clinically significant symptoms (mild night blindness, visual field constricted to 30 degrees, and scotopic and photopic ERG responses reduced to 30-60%). No extraocular symptoms were detected in any of the heterozygous female carriers. This family presents an example of two rare phenomena: X-linked dominant retinitis pigmentosa (with milder expression in females) and a rare combination of RP with recurrent respiratory infections due to PCD.

Variability in human cone topography assessed by adaptive optics scanning laser ophthalmoscopy

PubMed Central

Zhang, Tianjiao; Godara, Pooja; Blanco, Ernesto R.; Griffin, Russell L; Wang, Xiaolin; Curcio, Christine A.; Zhang, Yuhua

2015-01-01

Purpose To assess between- and within-individual variability of macular cone topography in the eyes of young adults. Design Observational case series. Methods Cone photoreceptors in 40 eyes of 20 subjects aged 19–29 years with normal maculae were imaged using a research adaptive optics scanning laser ophthalmoscope. Refractive errors ranged from −3.0 D to 0.63 D and differed by <0.50 D in fellow eyes. Cone density was assessed on a two-dimensional sampling grid over the central 2.4 mm × 2.4 mm. Between-individual variability was evaluated by coefficient of variation (CV). Within-individual variability was quantified by maximum difference and root-mean-square (RMS). Cones were cumulated over increasing eccentricity. Results Peak densities of foveal cones are 168,162 ± 23,529 cones/mm2 (mean ± SD) (CV = 0.14). The number of cones within the cone-dominated foveola (0.8–0.9 mm diameter) is 38,311 ± 2,319 (CV = 0.06). The RMS cone density difference between fellow eyes is 6.78%, and the maximum difference is 23.6%. Mixed model statistical analysis found no difference in the association between eccentricity and cone density in the superior/nasal (p=0.8503), superior/temporal (p=0.1551), inferior/nasal (p=0.8609), and inferior/temporal (p=0.6662) quadrants of fellow eyes. Conclusions New instrumentation imaged the smallest foveal cones, thus allowing accurate assignment of foveal centers and assessment of variability in macular cone density in a large sample of eyes. Though cone densities vary significantly in the fovea, the total number of foveolar cones are very similar both between- and within-subjects. Thus, the total number of foveolar cones may be an important measure of cone degeneration and loss. PMID:25935100

A study of factors affecting the human cone photoreceptor density measured by adaptive optics scanning laser ophthalmoscope

PubMed Central

Park, Sung Pyo; Chung, Jae Keun; Greenstein, Vivienne; Tsang, Stephen H.; Chang, Stanley

2015-01-01

To investigate the variation in human cone photoreceptor packing density with various demographic or clinical factors, cone packing density was measured using a Canon prototype adaptive optics scanning laser ophthalmoscope and compared as a function of retinal eccentricity, refractive error, axial length, age, gender, race/ethnicity and ocular dominance. We enrolled 192 eyes of 192 subjects with no ocular pathology. Cone packing density was measured at three different retinal eccentricities (0.5 mm, 1.0 mm, and 1.5 mm from the foveal center) along four meridians. Cone density decreased from 32,200 to 11,600 cells/mm2 with retinal eccentricity (0.5 mm to 1.5 mm from the fovea, P < 0.001). A trend towards a slightly negative correlation was observed between age and density (r = −0.117, P = 0.14). There was, however, a statistically significant negative correlation (r = −0.367, P = 0.003) between axial length and cone density. Gender, ocular dominance, and race/ethnicity were not important determinants of cone density (all, P > 0.05). In addition, to assess the spatial arrangement of the cone mosaics, the nearest-neighbor distances (NNDs) and the Voronoi domains were analyzed. The results of NND and Voronoi analysis were significantly correlated with the variation of the cone density. Average NND and Voronoi area were gradually increased (all, P ≤ 0.001) and the degree of regularity of the cone mosaics was decreased (P ≤ 0.001) with increasing retinal eccentricity. In conclusion, we demonstrated cone packing density decreases as a function of retinal eccentricity and axial length and the results of NND and Voronoi analysis is a useful index for cone mosaics arrangements. The results also serve as a reference for further studies designed to detect or monitor cone photoreceptors in patients with retinal diseases. PMID:23276813