Overexpression of Myocilin in the Drosophila Eye Activates the Unfolded Protein Response: Implications for Glaucoma

Glaucoma is the world's second leading cause of bilateral blindness with progressive loss of vision due to retinal ganglion cell death. Myocilin has been associated with congenital glaucoma and 2-4% of primary open angle glaucoma (POAG) cases, but the pathogenic mechanisms remain largely unknown. Among several hypotheses, activation of the unfolded protein response (UPR) has emerged as a possible disease mechanism.We used a transgenic Drosophila model to analyze whole-genome transcriptional profiles in flies that express human wild-type or mutant MYOC in their eyes. The transgenic flies display ocular fluid discharge, reflecting ocular hypertension, and a progressive decline in their behavioral responses to light. Transcriptional analysis shows that genes associated with the UPR, ubiquitination, and proteolysis, as well as metabolism of reactive oxygen species and photoreceptor activity undergo altered transcriptional regulation. Following up on the results from these transcriptional analyses, we used immunoblots to demonstrate the formation of MYOC aggregates and showed that the formation of such aggregates leads to induction of the UPR, as evident from activation of the fluorescent UPR marker, xbp1-EGFP. CONCLUSIONS / SIGNIFICANCE: Our results show that aggregation of MYOC in the endoplasmic reticulum activates the UPR, an evolutionarily conserved stress pathway that culminates in apoptosis. We infer from the Drosophila model that MYOC-associated ocular hypertension in the human eye may result from aggregation of MYOC and induction of the UPR in trabecular meshwork cells. This process could occur at a late age with wild-type MYOC, but might be accelerated by MYOC mutants to account for juvenile onset glaucoma

Dynamics of Shells

IASS 2008 Session: Dynamics of Shells -- "A seismic analysis of a modular shell system" by Youssef BELMOUDEN, Pierino LESTUZZI, Souad SELLAMI (Ecole Polytechnique Federale de Lausanne) -- "Earthquake analysis of cylindrical roof shells" by Shadi OSTAVARI DAILAMANI, James G. A. CROLL (University College London) -- "Interpretation of seismic response of cylindrical roof shells" by Shadi OSTAVARI DAILAMANI, James G. A. CROLL (University College London) -- "Dynamic cylindrical shell equations by power series expansions" by Anders M. HAGGLUND, Peter D. FOLKOW (Chalmers University of Technology) -- Dynamic equations for a homogenous, fully anisotropic, elastic plate Karl MAURITSSON, Anders BOSTROM, Peter D. FOLKOW (Chalmers University of Technology

Dried blood spot measurement of pregnancy-associated plasma protein A (PAPP-A) and free beta-subunit of human chorionic gonadotropin (beta-hCG) from a low-resource setting

ObjectivesThe objectives of the article is to compare pregnancy-associated plasma protein A (PAPP-A) and free -subunit of human chorionic gonadotropin (-hCG) concentrations in dried blood spots (DBSs) with serum of samples obtained from a public hospital in a low-resource setting and to evaluate their stability. MethodsSerum and DBS samples were obtained by venipuncture and finger prick from 50 pregnant participants in a cohort study in a public hospital in Accra, Ghana. PAPP-A and -hCG concentrations from serum and DBS were measured with an AutoDELFIA (R) (PerkinElmer, PerkinElmer, Turku, Finland) automatic immunoassay. Correlation and Passing-Bablok regression analyses were performed to compare marker levels. ResultsHigh correlation (>0.9) was observed for PAPP-A and -hCG levels between various sampling techniques. The -hCG concentration was stable between DBS and serum, PAPP-A concentration consistently lower in DBS. ConclusionOur findings suggest that -hCG can be reliably collected from DBS in low-resource tropical settings. The exact conditions of the clinical workflow necessary for reliable PAPP-A measurement in these settings need to be further developed in the future. These findings could have implications for prenatal screening programs feasibility in low-income and middle-income countries, as DBS provides an alternative minimally invasive sampling method, with advantages in sampling technique, stability, logistics, and potential application in low-resource settings. (c) 2015 John Wiley & Sons, Ltd

Dried blood spot measurement of pregnancy-associated plasma protein A (PAPP-A) and free beta-subunit of human chorionic gonadotropin (beta-hCG) from a low-resource setting

ObjectivesThe objectives of the article is to compare pregnancy-associated plasma protein A (PAPP-A) and free -subunit of human chorionic gonadotropin (-hCG) concentrations in dried blood spots (DBSs) with serum of samples obtained from a public hospital in a low-resource setting and to evaluate their stability. MethodsSerum and DBS samples were obtained by venipuncture and finger prick from 50 pregnant participants in a cohort study in a public hospital in Accra, Ghana. PAPP-A and -hCG concentrations from serum and DBS were measured with an AutoDELFIA (R) (PerkinElmer, PerkinElmer, Turku, Finland) automatic immunoassay. Correlation and Passing-Bablok regression analyses were performed to compare marker levels. ResultsHigh correlation (>0.9) was observed for PAPP-A and -hCG levels between various sampling techniques. The -hCG concentration was stable between DBS and serum, PAPP-A concentration consistently lower in DBS. ConclusionOur findings suggest that -hCG can be reliably collected from DBS in low-resource tropical settings. The exact conditions of the clinical workflow necessary for reliable PAPP-A measurement in these settings need to be further developed in the future. These findings could have implications for prenatal screening programs feasibility in low-income and middle-income countries, as DBS provides an alternative minimally invasive sampling method, with advantages in sampling technique, stability, logistics, and potential application in low-resource settings. (c) 2015 John Wiley & Sons, Ltd