Orestis Georgiou

Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes

Aims Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. Methods and results We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K+ currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). Conclusions These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart.

Full connectivity: corners, edges and faces

We develop a cluster expansion for the probability of full connectivity of high density random networks in confined geometries. In contrast to percolation phenomena at lower densities, boundary effects, which have previously been largely neglected, are not only relevant but dominant. We derive general analytical formulas that show a persistence of universality in a different form to percolation theory, and provide numerical confirmation. We also demonstrate the simplicity of our approach in three simple but instructive examples and discuss the practical benefits of its application to different models.

Low Power Wide Area Network Analysis: Can LoRa Scale?

Low power wide area (LPWA) networks are making spectacular progress from design, standardization, to commercialization. At this time of fast-paced adoption, it is of utmost importance to analyze how well these technologies will scale as the number of devices connected to the Internet of Things inevitably grows. In this letter, we provide a stochastic geometry framework for modeling the performance of a single gateway LoRa network, a leading LPWA technology. Our analysis formulates the unique peculiarities of LoRa, including its chirp spread-spectrum modulation technique, regulatory limitations on radio duty cycle, and use of ALOHA protocol on top, all of which are not as common in today’s commercial cellular networks. We show that the coverage probability drops exponentially as the number of end-devices grows due to interfering signals using the same spreading sequence. We conclude that this fundamental limiting factor is perhaps more significant toward LoRa scalability than for instance spectrum restrictions. Our derivations for co-spreading factor interference found in LoRa networks enables rigorous scalability analysis of such networks.

Impact of boundaries on fully connected random geometric networks

Many complex networks exhibit a percolation transition involving a macroscopic connected component, with universal features largely independent of the microscopic model and the macroscopic domain geometry. In contrast, we show that the transition to full connectivity is strongly influenced by details of the boundary, but observe an alternative form of universality. Our approach correctly distinguishes connectivity properties of networks in domains with equal bulk contributions. It also facilitates system design to promote or avoid full connectivity for diverse geometries in arbitrary dimension.

Survival probability for the stadium billiard

Abstract We consider the open stadium billiard, consisting of two semicircles joined by parallel straight sides with one hole situated somewhere on one of the sides. Due to the hyperbolic nature of the stadium billiard, the initial decay of trajectories, due to loss through the hole, appears exponential. However, some trajectories (bouncing ball orbits) persist and survive for long times and therefore form the main contribution to the survival probability function at long times. Using both numerical and analytical methods, we concur with previous studies that the long-time survival probability for a reasonably small hole drops like C o n s t a n t × ( t i m e ) − 1 ; here we obtain an explicit expression for the Constant.

Open mushrooms: stickiness revisited

We investigate mushroom billiards, a class of dynamical systems with sharply divided phase space. For typical values of the control parameter of the system ?, an infinite number of marginally unstable periodic orbits (MUPOs) exist making the system sticky in the sense that unstable orbits approach regular regions in phase space and thus exhibit quasi-regular behaviour for long periods of time. The problem of finding these MUPOs is expressed as the well-known problem of finding optimal rational approximations of a real number, subject to some system-specific constraints. By introducing a generalized mushroom and using properties of continued fractions, we describe for the first time a zero measure set of control parameter values ? (0, 1) for which all MUPOs are destroyed and therefore the system is less sticky, leading to a different power law exponent for the Poincar? recurrence time distribution statistics. The open mushroom (billiard with a hole) is then considered in order to quantify the stickiness exhibited due to MUPOs and exact leading order expressions for the algebraic decay of the survival probability function are calculated for mushrooms with triangular and rectangular stems. Numerical simulations are also performed which confirm our predictions for both sticky and less sticky mushrooms.

Transmission and reflection in the stadium billiard: Time-dependent asymmetric transport

The survival probability of the open stadium billiard with one hole on its boundary is well known to decay asymptotically as a power law. We investigate the transmission and reflection survival probabilities for the case of two holes placed asymmetrically. Classically, these distributions are shown to lose their algebraic decay tails depending on the choice of injecting hole, therefore exhibiting asymmetric transport. The mechanism behind this is explained while exact expressions are given and confirmed numerically. We propose a model for experimental observation of this effect using semiconductor nanostructures and comment on the relevant quantum time scales.

Connectivity of confined 3D networks with anisotropically radiating nodes

Nodes in ad hoc networks with randomly oriented directional antenna patterns typically have fewer short links and more long links which can bridge together otherwise isolated subnetworks. This network feature is known to improve overall connectivity in 2D random networks operating at low channel path loss. To this end, we advance recently established theoretical results to obtain analytic expressions for the mean degree of 3D networks for simple but practical anisotropic gain profiles, including those of patch, dipole and end-fire array antennas. Our analysis reveals that for homogeneous systems (i.e, neglecting boundary effects) directional radiation patterns are superior to the isotropic case only when the path loss exponent is less than the spatial dimension. Moreover, we establish that ad hoc networks utilizing directional transmit and isotropic receive antennas (or vice versa) are always sub-optimally connected regardless of the environment path loss. We extend our analysis to investigate inhomogeneous systems, and study the geometrical reasons why boundary effects cause directional radiating nodes to be at a disadvantage to isotropic ones. Finally, we discuss multi-directional gain patterns consisting of many equally spaced lobes which could be used to mitigate boundary effects and improve overall network connectivity.

Location, location, location: Border effects in interference limited ad hoc networks

Wireless networks are fundamentally limited by the intensity of the received signals and by their inherent interference. It is shown here that in finite ad hoc networks where node placement is modelled according to a Poisson point process and no carrier sensing is employed for medium access, the SINR received by nodes located at the border of the network deployment/operation region is on average greater than the rest. This is primarily due to the uneven interference landscape of such networks which is particularly kind to border nodes giving rise to all sorts of performance inhomogeneities and access unfairness. Using tools from stochastic geometry we quantify these spatial variations and provide closed form communication-theoretic results showing why the receivers location is so important.

More is less: Connectivity in fractal regions

Ad-hoc networks are often deployed in regions with complicated boundaries. We show that if the boundary is modeled as a fractal, a network requiring line of sight connections has the counterintuitive property that increasing the number of nodes decreases the full connection probability. We characterise this decay as a stretched exponential involving the fractal dimension of the boundary, and discuss mitigation strategies. Applications of this study include the analysis and design of sensor networks operating in rugged terrain (e.g. railway cuttings), mm-wave networks in industrial settings and vehicle-to-vehicle/vehicle-to-infrastructure networks in urban environments.