Antisense oligonucleotides: treatment strategies and cellular internalization

The clinical application of antisense oligonucleotides (ASOs) is becoming more of a reality as several drugs have been approved for the treatment of human disorders and many others are in various phases in development and clinical trials. ASOs are short DNA/RNA oligos which are heavily modified to increase their stability in biological fluids and retain the properties of creating RNA-RNA and DNA-RNA duplexes that knock-down or correct genetic expression. This review outlines several strategies that ASOs utilize for the treatment of various congenital diseases and syndromes that develop with aging. In addition, we discuss some of the mechanisms for specific non-targeted ASO internalization within cells

A Tool for Generating Controllable Variations of Musical Themes Using Variational Autoencoders with Latent Space Regularisation

A common musical composition practice is to develop musical pieces using variations of musical themes. In this study, we present an interactive tool which can generate variations of musical themes in real-time using a variational autoencoder model. Our tool is controllable using semantically meaningful musical attributes via latent space regularisation technique to increase the explainability of the model. The tool is integrated into an industry standard digital audio workstation - Ableton Live - using the Max4Live device framework and can run locally on an average personal CPU rather than requiring a costly GPU cluster. In this way we demonstrate how cutting-edge AI research can be integrated into the exiting workflows of professional and practising musicians for use in the real-world beyond the research lab

Lower Bounds for Structuring Unreliable Radio Networks

In this paper, we study lower bounds for randomized solutions to the maximal independent set (MIS) and connected dominating set (CDS) problems in the dual graph model of radio networks---a generalization of the standard graph-based model that now includes unreliable links controlled by an adversary. We begin by proving that a natural geographic constraint on the network topology is required to solve these problems efficiently (i.e., in time polylogarthmic in the network size). We then prove the importance of the assumption that nodes are provided advance knowledge of their reliable neighbors (i.e, neighbors connected by reliable links). Combined, these results answer an open question by proving that the efficient MIS and CDS algorithms from [Censor-Hillel, PODC 2011] are optimal with respect to their dual graph model assumptions. They also provide insight into what properties of an unreliable network enable efficient local computation.Comment: An extended abstract of this work appears in the 2014 proceedings of the International Symposium on Distributed Computing (DISC

Computing in Additive Networks with Bounded-Information Codes

This paper studies the theory of the additive wireless network model, in which the received signal is abstracted as an addition of the transmitted signals. Our central observation is that the crucial challenge for computing in this model is not high contention, as assumed previously, but rather guaranteeing a bounded amount of \emph{information} in each neighborhood per round, a property that we show is achievable using a new random coding technique. Technically, we provide efficient algorithms for fundamental distributed tasks in additive networks, such as solving various symmetry breaking problems, approximating network parameters, and solving an \emph{asymmetry revealing} problem such as computing a maximal input. The key method used is a novel random coding technique that allows a node to successfully decode the received information, as long as it does not contain too many distinct values. We then design our algorithms to produce a limited amount of information in each neighborhood in order to leverage our enriched toolbox for computing in additive networks

Structural Determinants for the Interactions of Chemically Modified Nucleic Acids with the Stabilin‑2 Clearance Receptor

The Stabilin receptors are systemic clearance receptors for some classes of chemically modified nucleic acid therapeutics. In this study, the recombinant human secreted ecto-domain of the small isoform of Stabilin-2 (s190) was purified from cell culture and evaluated for direct binding with a multitude of antisense oligonucleotides (ASOs) using a fluorescence polarizationbased assay. The tested ASOs varied in their backbone composition, modification of the ribose 2′ position, overall length of the oligo, and sequence of the nucleotide bases. A fully phosphorothioate (PS) ASO with a 5−10−5 pattern of flanking 2′-O-methoxyethyl modifications was then used to test the effects of pH and salt concentration on receptor binding. These tests concluded that the PS backbone was the primary determinant for ASO binding and that decreasing pH and increasing salt generally increased the rate of ligand dissociation and fit within the biological parameters expected of a constitutive recycling receptor. These results will be useful in the rational design of therapeutic oligonucleotides for enhancing their affinity or avoidance of the Stabilin receptors

Source amplitudes for active exterior cloaking

The active cloak comprises a discrete set of multipole sources that destructively interfere with an incident time harmonic scalar wave to produce zero total field over a finite spatial region. For a given number of sources and their positions in two dimensions it is shown that the multipole amplitudes can be expressed as infinite sums of the coefficients of the incident wave decomposed into regular Bessel functions. The field generated by the active sources vanishes in the infinite region exterior to a set of circles defined by the relative positions of the sources. The results provide a direct solution to the inverse problem of determining the source amplitudes. They also define a broad class of non-radiating discrete sources.Comment: 21 pages, 17 figure

Endosomal Escape of Antisense Oligonucleotides Internalized by Stabilin Receptors Is Regulated by Rab5C and EEA1 During Endosomal Maturation

Second-generation (Gen 2) Antisense oligonucleotides (ASOs) show increased nuclease stability and affinity for their RNA targets, which has translated to improved potency and therapeutic index in the clinic. Gen 2 ASOs are typically modified using the phosphorothioate (PS) backbone modification, which enhances ASO interactions with plasma, cell surface, and intracellular proteins. This facilitates ASO distribution to peripheral tissues and also promotes cellular uptake after injection into animals. Previous work identified that Stabilin receptors specifically internalize PS-ASOs in the sinusoidal endothelial cells of the liver and the spleen. By modulating expression of specific proteins involved in the trafficking and maturation of the endolysosomal compartments, we show that Rab5C and EEA1 in the early endosomal pathway, and Rab7A and lysobisphosphatidic acid in the late endosomal pathway, are important for trafficking of PS-ASOs and facilitate their escape from endolysosomal compartments after Stabilin-mediated internalization. In conclusion, this work identifies key ratelimiting proteins in the pathway for PS-ASO translocation and escape from the endosome

Speaking out about gender imbalance in invited speakers improves diversity.

Omissions of qualified women scientists from major meeting programs continue to occur despite a surge in articles indicating persistent gender-discriminatory practices in hiring and promotion, and calls for gender balance in conference organizing committees

Thermoacoustic tomography with detectors on an open curve: an efficient reconstruction algorithm

Practical applications of thermoacoustic tomography require numerical inversion of the spherical mean Radon transform with the centers of integration spheres occupying an open surface. Solution of this problem is needed (both in 2-D and 3-D) because frequently the region of interest cannot be completely surrounded by the detectors, as it happens, for example, in breast imaging. We present an efficient numerical algorithm for solving this problem in 2-D (similar methods are applicable in the 3-D case). Our method is based on the numerical approximation of plane waves by certain single layer potentials related to the acquisition geometry. After the densities of these potentials have been precomputed, each subsequent image reconstruction has the complexity of the regular filtration backprojection algorithm for the classical Radon transform. The peformance of the method is demonstrated in several numerical examples: one can see that the algorithm produces very accurate reconstructions if the data are accurate and sufficiently well sampled, on the other hand, it is sufficiently stable with respect to noise in the data

Resonance regimes of scattering by small bodies with impedance boundary conditions

The paper concerns scattering of plane waves by a bounded obstacle with complex valued impedance boundary conditions. We study the spectrum of the Neumann-to-Dirichlet operator for small wave numbers and long wave asymptotic behavior of the solutions of the scattering problem. The study includes the case when $k=0$ is an eigenvalue or a resonance. The transformation from the impedance to the Dirichlet boundary condition as impedance grows is described. A relation between poles and zeroes of the scattering matrix in the non-self adjoint case is established. The results are applied to a problem of scattering by an obstacle with a springy coating. The paper describes the dependence of the impedance on the properties of the material, that is on forces due to the deviation of the boundary of the obstacle from the equilibrium position