Objective To evaluate the association of subretinal hyper-reflective material (SHRM) with visual acuity (VA), geographic atrophy (GA) and scar in the Comparison of Age related Macular Degeneration Treatments Trials (CATT) Design Prospective cohort study within a randomized clinical trial. Participants The 1185 participants in CATT. Methods Participants were randomly assigned to ranibizumab or bevacizumab treatment monthly or as-needed. Masked readers graded scar and GA on fundus photography and fluorescein angiography images, SHRM on time domain (TD) and spectral domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1mm2, or outside the center 1mm2 were obtained on SD-OCT images at 56 (n=76) and 104 (n=66) weeks. VA was measured by certified examiners. Main Outcome Measures SHRM presence, location and size, and associations with VA, scar, and GA. Results Among all CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than eyes with SHRM that resolved (64% vs. 31%; p<0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n=76) and 104 (n=66), mean [SE] VA letter score was 73.5 [2.8], 73.1 [3.4], 65.3 [3.5], and 63.9 [3.7] when SHRM was absent, present outside the central 1mm2, present within the central 1mm2 but not the foveal center, or present at the foveal center (p=0.02). SHRM was present at the foveal center in 43 (30%), within the central 1mm2 in 21 (15%) and outside the central 1mm2 in 19 (13%). When SHRM was present, the median maximum height in microns under the fovea, within the central 1 mm2 including the fovea and anywhere within the scan was 86; 120; and 122, respectively. VA was decreased with greater SHRM height and width (p<0.05). Conclusions SHRM is common in eyes with NVAMD and often persists after anti-VEGF treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM height and width were associated with worse VA. SHRM is an important morphological biomarker in eyes with NVAMD.
We have created an open access web portal with pathosystem-wide resources and bioinformatics tools for the host citrus, the vector Asian citrus psyllid (ACP) and multiple pathogens including Ca. Liberibacter asiaticus. To the best of our knowledge, this is the first example of a database to use the pathosystem as a holistic framework to understand an insect transmitted plant disease. This endeavor integrates and enables the analysis of data sets generated by the community to study the citrus greening disease complex. Users can submit relevant data sets to enable sharing and allow the community to better analyze their data within an integrated system. The portal contains a variety of tools for omics data. Metabolic pathway databases, CitrusCyc and DiaphorinaCyc provide organism specific pathways that can be used to mine metabolomics, transcriptomics and proteomics results to identify pathways and regulatory mechanism involved in disease response. Psyllid Expression Network (PEN) contains expression profiles of ACP genes from multiple life stages, tissues, conditions and hosts. Citrus Expression Network (CEN) contains public expression data from multiple tissues and conditions for various citrus hosts. All tools like Apollo/JBrowse, Biocyc, Blast, CEN and PEN connect to a central database containing gene models for citrus, ACP and multiple Liberibacter pathogens. The portal also includes electrical penetration graph (EPG) recordings of ACP feeding on citrus, information about citrus rootstock trials and metabolomics data in addition to traditional omics data types with a goal of combining and mining all information related to a pathosystem. The portal includes user-friendly manual curation tools to allow the research community to continuously improve this knowledge base as more experimental research is published. Bulk downloads are available for all genome and annotation datasets from the FTP site (ftp://ftp.citrusgreening.org). The portal can be accessed at https://citrusgreening.org/.
The receptors responsible for the adenosine-mediated control of acetylcholine release from immunoaffinity-purified rat striatal cholinergic nerve terminals have been characterized. The relative affinities of three analogues for the inhibitory receptor were (R)-phenylisopropyladenosine greater than cyclohexyladenosine greater than N-ethylcarboxamidoadenosine (NECA), with binding being dependent of the presence of Mg2+ and inhibited by 5'-guanylylimidodiphosphate [Gpp(NH)p] and adenosine receptor antagonists. Adenosine A1 receptor agonists inhibited forskolin-stimulated cholinergic adenylate cyclase activity, with an IC50 of 0.5 nM for (R)-phenylisopropyladenosine and 500 nM for (S)-phenylisopropyladenosine. A1 agonists inhibited acetylcholine release at concentrations approximately 10% of those required to inhibit the cholinergic adenylate cyclase. High concentrations (1 microM) of adenosine A1 agonists were less effective in inhibiting both adenylate cyclase and acetylcholine release, due to the presence of a lower affinity stimulatory A2 receptor. Blockade of the A1 receptor with 8-cyclopentyl-1,3-dipropylxanthine revealed a half-maximal stimulation by NECA of the adenylate cyclase at 10 nM, and of acetylcholine release at approximately 100 nM. NECA-stimulated adenylate cyclase activity copurified with choline acetyltransferase in the preparation of the cholinergic nerve terminals, suggesting that the striatal A2 receptor is localized to cholinergic neurones. The possible role of feedback inhibitory and stimulatory receptors on cholinergic nerve terminals is discussed.
Cholinergic nerve terminals were affinity purified from rat caudate nucleus. On stimulation with both 22.6 mM KCl and 50 microM veratridine, ATP was released in a Ca2+-dependent manner. The molar ratio of released acetylcholine to ATP (9:1) was closer to that found in isolated cholinergic vesicles (7:1) than whole terminals (3:1). Extracellular [14C]ATP was rapidly metabolized by these terminals to adenosine and inosine via ectonucleotidases. The terminals had a saturable, high-affinity uptake mechanism for adenosine (Km = 16.6 microM). Veratridine stimulation also caused the Ca2+-dependent release of nucleosides in a dipyridamole-sensitive manner. Both theophylline treatment and inhibition of extracellular ATP breakdown resulted in increased ATP and nucleoside release. Extracellular adenosine was shown to inhibit acetylcholine release, probably via the A1 receptor. The role of extracellular purines at the cholinergic nerve terminal is discussed.
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