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31.
Dikla Bandah-Rozenfeld Rob W.J. Collin Eyal Banin Karlien L.M. Coene Anna M. Siemiatkowska Lina Zelinger Dirk J. Lefeber Inbar Erdinest Francesca Simonelli Ellen A.W. Blokland Caroline C.W. Klaver Raheel Qamar Sandro Banfi Dror Sharon Anneke I. den Hollander 《American journal of human genetics》2010,87(2):199-208
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases caused by progressive degeneration of the photoreceptor cells. Using autozygosity mapping, we identified two families, each with three affected siblings sharing large overlapping homozygous regions that harbored the IMPG2 gene on chromosome 3. Sequence analysis of IMPG2 in the two index cases revealed homozygous mutations cosegregating with the disease in the respective families: three affected siblings of Iraqi Jewish ancestry displayed a nonsense mutation, and a Dutch family displayed a 1.8 kb genomic deletion that removes exon 9 and results in the absence of seven amino acids in a conserved SEA domain of the IMPG2 protein. Transient transfection of COS-1 cells showed that a construct expressing the wild-type SEA domain is properly targeted to the plasma membrane, whereas the mutant lacking the seven amino acids appears to be retained in the endoplasmic reticulum. Mutation analysis in ten additional index cases that were of Dutch, Israeli, Italian, and Pakistani origin and had homozygous regions encompassing IMPG2 revealed five additional mutations; four nonsense mutations and one missense mutation affecting a highly conserved phenylalanine residue. Most patients with IMPG2 mutations showed an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity. The patient with the missense mutation, however, was diagnosed with maculopathy. The IMPG2 gene encodes the interphotoreceptor matrix proteoglycan IMPG2, which is a constituent of the interphotoreceptor matrix. Our data therefore show that mutations in a structural component of the interphotoreceptor matrix can cause arRP. 相似文献
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Traditionally, the information content of the neural response is quantified using statistics of the responses relative to stimulus onset time with the assumption that the brain uses onset time to infer stimulus identity. However, stimulus onset time must also be estimated by the brain, making the utility of such an approach questionable. How can stimulus onset be estimated from the neural responses with sufficient accuracy to ensure reliable stimulus identification? We address this question using the framework of colour coding by the archer fish retinal ganglion cell. We found that stimulus identity, “what”, can be estimated from the responses of best single cells with an accuracy comparable to that of the animal''s psychophysical estimation. However, to extract this information, an accurate estimation of stimulus onset is essential. We show that stimulus onset time, “when”, can be estimated using a linear-nonlinear readout mechanism that requires the response of a population of 100 cells. Thus, stimulus onset time can be estimated using a relatively simple readout. However, large nerve cell populations are required to achieve sufficient accuracy.
Authors Summary
In our interaction with the environment we are flooded with a stream of numerous objects and events. Our brain needs to understand the nature of these complex and rich stimuli in order to react. Research has shown ways in which a ‘what’ stimulus was presented can be encoded by the neural responses. However, to understand ‘what was the nature of the stimulus’ the brain needs to know ‘when’ the stimulus was presented. Here, we investigated how the onset of visual stimulus can be signalled by the retina to higher brain regions. We used archer fish as a framework to test the notion that the answer to the question of ‘when’ something has been presented lies within the larger cell population, whereas the answer to the question of ‘what’ has been presented may be found at the single-neuron level. The utility of the archer fish as model animal stems from its remarkable ability to shoot down insects settling on the foliage above the water level, and its ability to distinguish between artificial targets. Thus, the archer fish can provide the fish equivalent of a monkey or a human that can report psychophysical decisions. 相似文献33.
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Arabidopsis cryptochrome 2 completes its posttranslational life cycle in the nucleus 总被引:1,自引:0,他引:1 下载免费PDF全文
Yu X Klejnot J Zhao X Shalitin D Maymon M Yang H Lee J Liu X Lopez J Lin C 《The Plant cell》2007,19(10):3146-3156
CRY2 is a blue light receptor regulating light inhibition of hypocotyl elongation and photoperiodic flowering in Arabidopsis thaliana. The CRY2 protein is found primarily in the nucleus, and it is known to undergo blue light-dependent phosphorylation and degradation. However, the subcellular location where CRY2 exerts its function or undergoes blue light-dependent phosphorylation and degradation remains unclear. In this study, we analyzed the function and regulation of conditionally nuclear-localized CRY2. Our results show that CRY2 mediates blue light inhibition of hypocotyl elongation and photoperiodic promotion of floral initiation in the nucleus. Consistent with this result and a hypothesis that blue light-dependent phosphorylation is associated with CRY2 function, we demonstrate that CRY2 undergoes blue light-dependent phosphorylation in the nucleus. CRY2 phosphorylation is required for blue light-dependent CRY2 degradation, but only a limited quantity of CRY2 is phosphorylated at any given moment in seedlings exposed to blue light, which explains why continuous blue light illumination is required for CRY2 degradation. Finally, we showed that CRY2 is ubiquitinated in response to blue light and that ubiquitinated CRY2 is degraded by the 26S proteasome in the nucleus. These findings demonstrate that a photoreceptor can complete its posttranslational life cycle (from protein modification, to function, to degradation) inside the nucleus. 相似文献
35.
Paraoxonases are associated with intestinal inflammatory diseases and intracellularly localized to the endoplasmic reticulum 总被引:2,自引:0,他引:2
Rothem L Hartman C Dahan A Lachter J Eliakim R Shamir R 《Free radical biology & medicine》2007,43(5):730-739
We demonstrated previously that the paraoxonase (PON1/2/3) genes and proteins are expressed in human intestinal biopsies and in Caco-2 cells. The current study aims were to explore whether PON1/2/3 expression is different in inflammatory bowel diseases (IBD) or celiac disease compared to healthy controls, and to explore the intracellular localization of PON1/2/3. Our results showed that significantly fewer biopsies expressed PON1 and PON3 in the duodenum of celiac patients (PON1, P<0.0001; PON3, P=0.03), in the terminal ileum of Crohn's patients (PON1, P=0.001; PON3, P=0.008), and in the colon of UC patients (PON1, P=0.02; PON3, P=0.06) compared to controls. Since all three disorders share markedly elevated inflammatory mediators we explored the PON1/2/3 mRNA expression on cytokine stimulation. No changes were observed in Caco-2 and HT29 cells. Immunofluorescence experiments localized PON1/2/3 exclusively to the endoplasmic reticulum (ER) in both CaCo-2 and HT29 cells. These results demonstrate for the first time a novel relationship between PON1 and PON3 expression and several inflammatory gastrointestinal disorders. Together with the localization of PON1/2/3 enzymes to the ER, it may be suggested that PON1/2/3 may have extracellular functions as part of the host response in IBD and celiac disease. 相似文献
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37.
Genomic technology has completely changed the way in which we are able to diagnose human genetic mutations. Genomic techniques such as the polymerase chain reaction, linkage analysis, Sanger sequencing, and most recently, massively parallel sequencing, have allowed researchers and clinicians to identify mutations for patients with Pendred syndrome and DFNB4 non-syndromic hearing loss. While thus far most of the mutations have been in the SLC26A4 gene coding for the pendrin protein, other genetic mutations may contribute to these phenotypes as well. Furthermore, mouse models for deafness have been invaluable to help determine the mechanisms for SLC26A4-associated deafness. Further work in these areas of research will help define genotype-phenotype correlations and develop methods for therapy in the future. 相似文献
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39.
Most biological phospholipids contain at least one unsaturated alkyl chain. However, few order parameters of unsaturated lipids have been determined because of the difficulty associated with isotopic labeling of a double bond. Dipolar recoupling on axis with scaling and shape preservation (DROSS) is a solid-state nuclear magnetic resonance technique optimized for measuring 1H–13C dipolar couplings and order parameters in lipid membranes in the fluid phase. It has been used to determine the order profile of 1,2-dimyristoyl-sn-glycero-3-phosphocholine hydrated membranes. Here, we show an application for the measurement of local order parameters in multilamellar vesicles containing unsaturated lipids. Taking advantage of the very good 13C chemical shift dispersion, one can easily follow the segmental order along the acyl chains and, particularly, around the double bonds where we have been able to determine the previously misassigned order parameters of each acyl chain of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). We have followed the variation of such order profiles with temperature, unsaturation content and cholesterol addition. We have found that the phase formed by DOPC with 30% cholesterol is analogous to the liquid-ordered (lo) phase. Because these experiments do not require isotopic enrichment, this technique can, in principle, be applied to natural lipids and biomembranes.Electronic Supplementary Material Supplementary material is available for this article at . 相似文献
40.