Preferential regulation of miRNA targets by environmental chemicals in the human genome

<p>Abstract</p> <p>Background</p> <p>microRNAs (miRNAs) represent a class of small (typically 22 nucleotides in length) non-coding RNAs that can degrade their target mRNAs or block their translation. Recent disease research showed the exposure to some environmental chemicals (ECs) can regulate the expression patterns of miRNAs, which raises the intriguing question of how miRNAs and their targets cope with the exposure to ECs throughout the genome.</p> <p>Results</p> <p>In this study, we comprehensively analyzed the properties of genes regulated by ECs (EC-genes) and found miRNA targets were significantly enriched among the EC-genes. Compared with the non-miRNA-targets, miRNA targets were roughly twice as likely to be EC-genes. By investigating the collection methods and other properties of the EC-genes, we demonstrated that the enrichment of miRNA targets was not attributed to either the potential collection bias of EC-genes, the presence of paralogs, longer 3'UTRs or more conserved 3'UTRs. Finally, we identified 1,842 significant concurrent interactions between 407 miRNAs and 497 ECs. This association network of miRNAs-ECs was highly modular and could be separated into 14 interconnected modules. In each module, miRNAs and ECs were closely connected, providing a good method to design accurate miRNA markers for ECs in toxicology research.</p> <p>Conclusions</p> <p>Our analyses indicated that miRNAs and their targets played important roles in cellular responses to ECs. Association analyses of miRNAs and ECs will help to broaden the understanding of the pathogenesis of such chemical components.</p

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2. We further demonstrate that this mutation results in constitutive activation of the guanine nucleotide exchange factor (GEF) activity of IQSEC2 resulting in increased production of the active form of Arf6. In a CRISPR generated mouse model of the A350V IQSEC2 mutation, we demonstrate that the surface expression of GluA2 AMPA receptors in mouse hippocampal tissue was significantly reduced in A350V IQSEC2 mutant mice compared to wild type IQSEC2 mice and that there is a significant reduction in basal synaptic transmission in the hippocampus of A350V IQSEC2 mice compared to wild type IQSEC2 mice. Finally, the A350V IQSEC2 mice demonstrated increased activity, abnormal social behavior and learning as compared to wild type IQSEC2 mice. These findings suggest a model of how the A350V mutation in IQSEC2 may mediate disease with implications for targets for drug therapy. These studies provide a paradigm for a personalized approach to precision therapy for a disease that heretofore has no therapy

Investigation of the semi-strip’s stress state in the case of steady-state oscillations

The elastic semi-strip under the dynamic load concentrated at the centre of the semi-strip’s short edge is considered. The lateral sides of the semi-strip are fixed. The case of steady-state oscillations is considered. The initial problem is reduced to the one-dimensional problem with the help of the semi-infinite sin-, cos-Fourier’s transform. The one-dimensional problem is formulated in the vector form. Its solution is constructed as a superposition of the general solution for the homogeneous equation and the partial solution for the inhomogeneous equation. The general solution for the homogeneous vector equation is found with the help of the matrix differential calculations. The partial solution is expressed through Green’s matrixfunction, which is constructed as the bilinear expansion. The inverse Fourier’s transform is applied to the derived expressions for the displacements. The solving of the initial problem is reduced to the solving of the singular integral equation. Its solution is searched as the series of the orthogonal Chebyshev polynomials of the second kind. The orthogonalization method is used for the solving of the singular integral equation. The stress-deformable state of the semi-strip is investigated regarding both the frequency of the applied load, and the load segment’s length.Key words: semi-strip, steady-state oscillations, Fourier’s transform, Green’s matrix-function, singular integral equation.Pages of the article in the issue: 54-57Language of the article: Ukrainia

Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders

The four voltage-gated sodium channels SCN1/2/3/8A have been associated with heterogeneous types of developmental disorders, each presenting with disease specific temporal and cell type specific gene expression. Using single-cell RNA sequencing transcriptomic data from humans and mice, we observe that SCNIA is predominantly expressed in inhibitory neurons. In contrast, SCN2/3/8A are profoundly expressed in excitatory neurons with SCN2/3A starting prenatally, followed by SCN1/8A neonatally. In contrast to previous observations from low resolution RNA screens, we observe that all four genes are expressed in both excitatory and inhibitory neurons, however, exhibit differential expression strength. These findings provide molecular evidence, at single-cell resolution, to support the hypothesis that the excitatory/inhibitory (E/I) neuronal expression ratios of sodium channels are important regulatory mechanisms underlying brain homeostasis and neurological diseases. Modulating the Ell expression balance within cell types of sodium channels could serve as a potential strategy to develop targeted treatment for Nay-associated neuronal developmental disorders. (C) 2019 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society

AUV-enabled adaptive underwater surveying for optimal data collection

A new adaptive strategy for performing data collection with a sonar-equipped autonomous underwater vehicle (AUV) is proposed. The approach is general in the sense that it is applicable to a wide range of underwater tasks that rely on subsequent processing of side-looking sonar imagery. By intelligently allocating resources and immediately reacting to the data collected in-mission, the proposed approach simultaneously maximizes the information content in the data and decreases overall survey time. These improvements are achieved by adapting the AUV route to prevent portions of the mission area from being either characterized by poor image quality or obscured by shadows caused by sand ripples. The peak correlation of consecutive sonar returns is used as a measure for image quality. To detect the presence of and estimate the orientation of sand ripples, a new innovative algorithm is developed. The components of the overall data-driven path-planning algorithm are purposely constructed to permit fast real-time execution with only minimal AUV onboard processing capabilities. Experimental results based on real sonar data collected at sea are used to demonstrate the promise of the proposed approach