Gene therapy for inherited retinal diseases has been shown to ameliorate functional and structural defects in both animal models and in human clinical trials. X-linked retinoschisis (XLRS) is an early-age onset macular dystrophy resulting from loss of an extracellular matrix protein (RS1). In preparation for a human clinical gene therapy trial, we conducted a dose-range efficacy study of the clinical vector, a self-complementary AAV vector delivering a human retinoschisin (RS1) gene under control of the RS1 promoter and an interphotoreceptor binding protein enhancer (AAV8-scRS/IRBPhRS), in the retinoschisin knockout (Rs1-KO) mouse. The therapeutic vector at 1x106 – 2.5x109 (1E6-2.5E9) vector genomes (vg)/eye or vehicle was administered to one eye of 229 male Rs1-KO mice by intravitreal injection at 22 ± 3 days postnatal age (PN). Analysis of retinal function (dark-adapted electroretinogram, ERG), structure (cavities and outer nuclear layer thickness) by in vivo retinal imaging using optical coherence tomography (OCT), and retinal immunohistochemistry (IHC) for RS1 was done 3 to 4 months and/or 6 to 9 months post-injection (PI). RS1 IHC staining was dose-dependent across doses ≥ 1E7 vg/eye, and the threshold for significant improvement in all measures of retinal structure and function was 1E8 vg/eye. Higher doses, however, did not produce additional improvement. At all doses showing efficacy, RS1 staining in Rs1-KO mouse was less than in wild type (WT) mice. Improvement in the ERG and RS1 staining was unchanged or greater at 6 to 9 months than at 3 to 4 months PI. This study demonstrates that vitreal administration of AAV8 scRS/IRBPhRS produces significant improvement in retinal structure and function in the mouse model of XLRS over a vector dose range that can be extended to a human trial. It indicates that fully normal RS1 expression is not necessary for a therapeutic effect.

Background: Coronary artery disease (CAD) is a cardiovascular disease with significant personal health and socioeconomic consequences. The biological functions of decanoic acid and the pathogenesis of CAD overlap considerably; however, studies exploring their relationship are limited. Methods: Data from 34,186 Americans from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2018 were analyzed. The relationship between dietary decanoic acid (DDA) and CAD prevalence was explored using weighted multivariate logistic regression models, generalized summation models, and fitted smoothing curves. Stratified analyses and interaction tests were conducted to explore the potential modifiers between them. Results: DDA was negatively associated with CAD prevalence, with each 1 g/d increase in the DDA being associated with a 21% reduction in CAD prevalence (odds ratio (OR) 0.79, 95% confidence interval (CI) 0.61–1.02). This relationship persisted after log10 and trinomial transformations, respectively. The OR after log10 transformation was 0.81 (95% CI 0.69–0.96), and the OR for tertile 3 compared with tertile 1 was 0.83 (95% CI 0.69–1.00). The subgroup analyses found this relationship to be significant among males and non-Hispanic white individuals, and there was a significant interaction (interaction p-values of 0.011 and 0.012, respectively). Conclusions: DDA was negatively associated with the prevalence of CAD, and both sex and race may modify this relationship.

As for inverse problem, there exist lots of traditional mathematic and physical methods. In recent years, the burgeoning evolutionary algorithms have been widely utilized in many areas. Their global optimization, parallelism, and effectiveness are widely applied to functional optimization problems. A method based on gene expression programming is presented in this paper for identifying the parameter in inverse problems. The results show that the new method is very effective for solving the inverse problem even for the case with large noise in the observation data.

Iodine is a vital trace element in the human body and is associated with several important coronary artery disease (CAD) risk factors. We aimed to explore the correlation between urinary iodine concentration (UIC) and CAD. Methods: Data from 15793 US adults in the National Health and Nutrition Examination Survey (NHANES) (2003–2018) were analyzed. We conducted multivariable logistic regression models and fitted smoothing curves to study the correlation between UIC and CAD. Furthermore, we performed subgroup analysis to investigate possible effect modifiers between them. Results: We found a J-shaped association between UIC and CAD, with an inflection point at Lg UIC=2.65 μg/L. This result indicated a neutral association (OR 0.89; 95% CI 0.68–1.16) between UIC and CAD as Lg UIC <2.65 μg/L, but the per natural Lg [UIC] increment was OR 2.29; 95% CI 1.53–3.43 as Lg UIC≥2.65 μg/L. An interaction between diabetes and UIC might exist. The increase in UIC results in an increase in CAD prevalence (OR 1.84, 95% CI 1.32–2.58) in diabetes but results in little to no difference in non-diabetes (OR 0.98, 95% CI 0.77–1.25). Conclusion: The J-shaped correlation between UIC and CAD and the interaction between diabetes and UIC should be confirmed in a prospective study with a series of UIC measurements. If excessive iodine precedes CAD, then this new finding could guide clinical practice and prevent iodine deficiency from being overcorrected.

Unique morphologies of rod and cone photoreceptor presynaptic terminals permit the formation of synapses onto interneurons during retina development. We integrated multiple “omics” datasets of developing rod and S-cone-like photoreceptors and identified 719 genes that are regulated by NRL and CRX, critical transcriptional regulators of rod differentiation, as candidates for controlling presynapse morphology. In vivo knockdown of 72 candidate genes in the developing retina uncovered 26 genes that alter size and/or positioning of rod spherules in the outer plexiform layer. Co-expression of seven cDNAs with their cognate shRNAs rescued the rod presynapse phenotype. Loss of function of four genes in germline or by an AAV-mediated CRISPR/Cas9 strategy validated RNAi screen findings. A protein interaction network analysis of the 26 positive effectors revealed additional candidates in the NRL/CRX-regulated presynapse morphology-associated gene network. Follow-up knockdowns of two novel candidates support the proposed network. Our studies demonstrate a requirement of multiple components in a modular network for rod presynapse morphogenesis and provide a functional genomic framework for deciphering genetic determinants of morphological specification during development. Author Summary: The relationship between neuronal morphology and function has been recognized for over 100 years. However, we still have poor understanding of genes and proteins that control morphogenesis of a specific neuron. In the current study, we address this connection between gene expression and neural morphology by identifying and knocking down a subset of expressed genes in rod photoreceptors. We ascertained a number of candidate genes controlling photoreceptor pre-synaptic terminal morphology, which is necessary for its connection with second-order neurons in the retinal circuit. Furthermore, we have curated a more plausible network of genes, either identified in our study or predicted, that are enriched for processes underlying photoreceptor morphogenesis. We suggest that our work will provide a framework for dissecting genetic basis of neuronal architecture and assist in better design of cell replacement therapies for retinal degeneration.