• Kappel Olson posted an update 1 year, 5 months ago

    Simvastatin’s effects were abrogated by miR-652-3p overexpression and phenocopied by miR-652-3p inhibition. The dyslipidemic mouse model exhibited increased miR-652-3p and decreased ISL1 protein levels in the endothelium, effects opposed by simvastatin or miR-652-3p inhibition. The impact of simvastatin in vivo was abolished by overexpressing miR-652-3p or knocking-down ISL1. The rat model of dyslipidemia exhibited a similar pattern of miR-652-3p upregulation, attenuated ISL1 protein levels, decreased eNOS activation, and decreased NO production, effects mitigated by simvastatin. CONCLUSIONS Dyslipidemia upregulates endothelial miR-652-3p, which decreases ISL1 protein levels, eNOS activation, and NO production. Simvastatin therapy lowers endothelial miR-652-3p expression to protect endothelial function under dyslipidemic conditions. The interaction between apoptosis-inducing factor (AIF) and cyclophilin A (CypA) has been shown to contribute to caspase-independent apoptosis. Blocking the AIF/CypA interaction protects against glutamate-induced neuronal cell death in vitro, and the purpose of this study was to determine the in vivo effect of an AIF/CypA interaction blocking peptide (AIF(370-394)-TAT) on neonatal mouse brain injury after hypoxia-ischemia (HI). The pups were treated with AIF (370-394)-TAT peptide intranasally prior to HI. Brain injury was significantly reduced at 72 h after HI in the AIF(370-394)-TAT peptide treatment group compared to vehicle-only treatment for both the gray matter and the subcortical white matter, and the neuroprotection was more pronounced in males than in females. Neuronal cell death was evaluated in males at 8 h and 24 h post-HI, and it was decreased significantly in the CA1 region of the hippocampus and the nucleus habenularis region after AIF(370-394)-TAT treatment. Caspase-independent apoptosis was decreased in the cortex, striatum, and nucleus habenularis after AIF(370-394)-TAT treatment, but no significant change was found on caspase-dependent apoptosis as indicated by the number of active caspase-3-labeled cells. Further analysis showed that both AIF and CypA nuclear accumulation were decreased after treatment with the AIF(370-394)-TAT peptide. These results suggest that AIF(370-394)-TAT inhibited AIF/CypA translocation to the nucleus and reduced HI-induced caspase-independent apoptosis and brain injury in young male mice, suggesting that blocking AIF/CypA might be a potential therapeutic target for neonatal brain injury. Phosphorylation is the most important post-translational modification of proteins in many cells, including neurons. Phosphoproteomics is a relatively new technique for comprehensively identifying phosphorylation sites in the whole proteome of a given system. We applied this method to developmental neurobiology research to understand the signaling pathways that regulate the mammalian growth cone, which is formed at the tips of developing neurites to ensure accurate neuronal network formation. Using this powerful technique, we identified at least four phosphorylation sites tightly associated with axon growth. Because phosphoproteomic results include relatively large numbers of phosphopeptides, the data are typically analyzed using bioinformatics. We utilized three bioinformatics tools to identify the responsible protein kinases, the putative functions of the phosphorylated protein groups, and the evolutional aspects of the phosphorylated proteins. Collectively, these data indicate phosphoproteomics is a cutting-edge tool for neuroscience research. PURPOSE To quantitatively measure hyperreflective foci (HRF) during the progression of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) using deep learning (DL) and investigate the association with local and global growth of GA. METHODS Eyes with GA were prospectively included. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence images were acquired every 6 months. DW71177 cell line A 500-μm wide junctional zone adjacent to the GA border was delineated and HRF were quantified using a validated DL algorithm. HRF concentrations in progressing and non-progressing areas, as well as correlations between HRF quantifications and global and local GA progression were assessed. RESULTS A total of 491 SD-OCT volumes from 87 eyes of 54 patients were assessed with a median follow-up of 28 months. Two-thirds of HRF were localized within a millimeter adjacent to the GA border. HRF concentration was positively correlated with GA progression in unifocal and multifocal GA (all p.05). CONCLUSION Advanced AI methods in high resolution retinal imaging allows to identify, localize and quantify biomarkers such as HRF. Increased HRF concentrations in the junctional zone and future macular atrophy may represent progressive migration and loss of retinal pigment epithelium. AI-based biomarker monitoring may pave the way into the era of individualized risk assessment and objective decision making processes. PURPOSE To evaluate functional vision, general health status, and work productivity in individuals with and without dry eye disease (DED). DESIGN Cross-sectional study. METHODS SettingGeneral US population (2018). STUDY POPULATION Adults ≥18 years with (n = 1003) or without (n = 1006) self-reported DED. MAIN OUTCOME MEASURES All respondents completed the National Eye Institute Visual Function Questionnaire (VFQ) and the EuroQol 5-dimensions 5-levels (EQ-5D-5L). All respondents with DED completed the eye dryness score (EDS) visual analogue scale, Ocular Comfort Index (OCI), and Work Productivity and Activity Impairment (WPAI) questionnaire. Half of respondents with DED completed the Impact of Dry Eye on Everyday Life (IDEEL) questionnaire; the other half completed the Dry Eye Questionnaire 5 (DEQ-5) and Standardized Patient Evaluation of Eye Dryness (SPEED), McMonnies, and Symptom Assessment in Dry Eye (SANDE) questionnaires. All analyses were descriptive. RESULTS Respondents with DED reported more comorbidities, greater exposure to adverse environmental conditions, and lower (worse) mean (standard deviation) scores on the modified Rasch-scored 28-item VFQ (VFQ-28R) total score (68.8 [11.9] vs 81.2 [12.7]) and EQ-5D-5L (0.82 [0.13] vs 0.88 [0.14]) than respondents without DED. Respondents with DED and EDS≥60 (highest discomfort) fared worse on OCI, VFQ-28R, and WPAI than respondents with DED and EDS less then 40 (lowest discomfort). Similar findings were observed with IDEEL, DEQ-5, SPEED, McMonnies, and SANDE scores. CONCLUSIONS There is a substantial burden of DED on functional vision, general health status, and productivity and further, these parameters appear to worsen with increasing EDS.

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