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Shannon E. Boye Sanford L. Boye Jijing Pang Renee Ryals Drew Everhart Yumiko Umino Andy W. Neeley Joseph Besharse Robert Barlow William W. Hauswirth 《PloS one》2010,5(6)
Background
Recessive mutations in guanylate cyclase-1 (Gucy2d) are associated with severe, early onset Leber congenital amaurosis-1(LCA1). Gucy2d encodes guanylate cyclase (GC1) is expressed in photoreceptor outer segment membranes and produces cGMP in these cells. LCA1 patients present in infancy with severely impaired vision and extinguished electroretinogram (ERG) but retain some photoreceptors in both their macular and peripheral retina for years. Like LCA1 patients, loss of cone function in the GC1 knockout (GC1KO) mouse precedes cone degeneration. The purpose of this study was to test whether delivery of functional GC1 to cone cells of the postnatal GC1KO mouse could restore function to these cells.Methodology/Principal Findings
Serotype 5 AAV vectors containing either a photoreceptor-specific, rhodopsin kinase (hGRK1) or ubiquitous (smCBA) promoter driving expression of wild type murine GC1 were subretinally delivered to one eye of P14 GC1KO mice. Visual function (ERG) was analyzed in treated and untreated eyes until 3 months post injection. AAV-treated, isogenic wild type and uninjected control mice were evaluated for restoration of visual behavior using optomotor testing. At 3 months post injection, all animals were sacrificed, and their treated and untreated retinas assayed for expression of GC1 and localization of cone arrestin. Cone-mediated function was restored to treated eyes of GC1KO mice (ERG amplitudes were ∼45% of normal). Treatment effect was stable for at least 3 months. Robust improvements in cone-mediated visual behavior were also observed, with responses of treated mice being similar or identical to that of wild type mice. AAV-vectored GC1 expression was found in photoreceptors and cone cells were preserved in treated retinas.Conclusions/Significance
This is the first demonstration of gene-based restoration of both visual function/vision-elicited behavior and cone preservation in a mammalian model of GC1 deficiency. Importantly, results were obtained using a well characterized, clinically relevant AAV vector. These results lay the ground work for the development of an AAV-based gene therapy vector for the treatment of LCA1. 相似文献24.
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Bortezomib is a chemotherapeutic agent used to treat several cancers; however, it exhibits severe side effects in testicular tissue. We investigated the use of agomelatine to prevent testicular tissue damage caused by bortezomib. We used 36 male Sprague-Dawley rats divided randomly into six equal groups: group 1, no treatment control; group 2, agomelatine treatment only; group 3, bortezomib treatment only for 48 h; group 4, bortezomib + agomelatine treatment for 48 h; group 5, bortezomib treatment only for 72 h; and group 6, bortezomib + agomelatine treatment for 72 h. After treatments, the rats were sacrificed and testicular tissue was harvested. Lipid oxidation (LPO) and superoxide dismutase (SOD) levels in the tissues were determined using biochemical methods. Tissue samples also were examined using histopathological and immunohistochemical techniques. The LPO level was increased, while the SOD level was decreased in the bortezomib treated groups. We found that agomelatine treatment normalized LPO and SOD activities in the bortezomib treated groups. In the spermatogonia and Sertoli cells, the staining density of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and caspase 3 were decreased in the bortezomib + agomelatine groups at both 48 and 72 h compared to bortezomib only treated groups. We observed maturation arrest, basal membrane thickening, increase in inflammatory cells and connective tissue, and edema between germ cells in the bortezomib only treated groups. By contrast, normal basal membrane, less edema and more normal maturation were observed in the bortezomib + agomelatine groups at 48 and 72 h. We found that agomelatine reduced the damaging effects of bortezomib. The use of agomelatine to prevent bortezomib induced testicular tissue damage in human patients should be investigated further. 相似文献
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The authors investigated two issues among overweight men and women in the U.S.: 1) what is the influence of the self-expressed intention to lose weight in the presence of other potential predictors of loss and 2) what are easily identifiable predictors of intentional weight loss during a 1-year recall period. The sample consisted of 1996 overweight men (body mass index (BMI ≥ 27.8 kg/m2) and 2586 overweight women (BMI ≥ 27.3 kg/m2) who answered questions regarding 1-year weight change in a Current Health Topic supplement of the population-based 1989 National Health Interview Survey. Of these overweight persons, 56.8% of men and 72.1% of women attempted to lose weight during the previous year. The most important characteristic associated with weight loss was the expressed intention itself. For any weight loss, the odds ratios (95% confidence intervals) for intention were 4.6 (3.6?5.9) for men and 3.8 (2.8?5.0) for women. Controlling for other factors reduced the odds only slightly, to 4.3 for men and 3.5 for women. Among women, older age, having a greater frequency of blood pressure checks, and being in poorer health reduced the influence of intent as a predictor of loss. To address the second objective, the identification of predictors of intentional 1-year weight loss, analysis was restricted to overweight persons who attempted to lose weight. For both sexes, statistically significant predictors (p<0.05) included never being married, smoking, higher BMI, being diabetic, and having a higher number of blood pressure checks. Being divorced or separated was predictive of weight loss in men only. Also, men were more likely to achieve weight loss than women. In conclusion, 1-year weight loss among the overweight was primarily a function of the intention to lose weight, although other factors contributed to determine whether weight loss was achieved. 相似文献
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Bianca V Gapp Tomasz Konopka Thomas Penz Vineet Dalal Tilmann Bürckstümmer Christoph Bock Sebastian MB Nijman 《Molecular systems biology》2016,12(8)
Reverse genetic screens have driven gene annotation and target discovery in model organisms. However, many disease‐relevant genotypes and phenotypes cannot be studied in lower organisms. It is therefore essential to overcome technical hurdles associated with large‐scale reverse genetics in human cells. Here, we establish a reverse genetic approach based on highly robust and sensitive multiplexed RNA sequencing of mutant human cells. We conduct 10 parallel screens using a collection of engineered haploid isogenic cell lines with knockouts covering tyrosine kinases and identify known and unexpected effects on signaling pathways. Our study provides proof of concept for a scalable approach to link genotype to phenotype in human cells, which has broad applications. In particular, it clears the way for systematic phenotyping of still poorly characterized human genes and for systematic study of uncharacterized genomic features associated with human disease. 相似文献