Role of RNA Motifs in RNA Interaction with Membrane Lipid Rafts: Implications for Therapeutic Applications of Exosomal RNAs

RNA motifs may promote interactions with exosomes (EXO-motifs) and lipid rafts (RAFT-motifs) that are enriched in exosomal membranes. These interactions can promote selective RNA loading into exosomes. We quantified the affinity between RNA aptamers containing various EXO- and RAFT-motifs and membrane lipid rafts in a liposome model of exosomes by determining the dissociation constants. Analysis of the secondary structure of RNA molecules provided data about the possible location of EXO- and RAFT-motifs within the RNA structure. The affinity of RNAs containing RAFT-motifs (UUGU, UCCC, CUCC, CCCU) and some EXO-motifs (CCCU, UCCU) to rafted liposomes is higher in comparison to aptamers without these motifs, suggesting direct RNA-exosome interaction. We have confirmed these results through the determination of the dissociation constant values of exosome-RNA aptamer complexes. RNAs containing EXO-motifs GGAG or UGAG have substantially lower affinity to lipid rafts, suggesting indirect RNA-exosome interaction via RNA binding proteins. Bioinformatics analysis revealed RNA aptamers containing both raft- and miRNA-binding motifs and involvement of raft-binding motifs UCCCU and CUCCC. A strategy is proposed for using functional RNA aptamers (fRNAa) containing both RAFT-motif and a therapeutic motif (e.g., miRNA inhibitor) to selectively introduce RNAs into exosomes for fRNAa delivery to target cells for personalized therapy.     

Blockade of Serotonin 5-HT6 Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT₆ receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT₆ receptors contribute to increased mTOR activity in the brain of Nf1^+/− mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT₆ receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1^+/− mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT₆ receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT₆ receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients.     

Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer

The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to the N⁶ atom of adenine. We have screened a library of 4000 analogues and derivatives of the adenosine moiety of SAM by high-throughput docking into METTL3. Two series of adenine derivatives were identified in silico, and the binding mode of six of the predicted inhibitors was validated by protein crystallography. Two compounds, one for each series, show good ligand efficiency. We propose a route for their further development into potent and selective inhibitors of METTL3.     

Long-term cyclability of nanostructured LiFePO4

Amorphous LiFePO₄ was obtained by lithiation of FePO₄ synthesized by spontaneous precipitation from equimolar aqueous solutions of Fe(NH₄)₂(SO₄)₂·6H₂O and NH₄H₂PO₄, using hydrogen peroxide as oxidizing agent. Nano-crystalline LiFePO₄ was obtained by heating amorphous nano-sized LiFePO₄ for different periods of time. The materials were characterized by TG, DTA, X-ray powder diffraction, scanning electron microscopy (SEM) and BET. All materials showed very good electrochemical performance in terms of energy and power density. Upon cycling, a capacity fading affected the materials, thus reducing the electrochemical performance. Nevertheless, the fading decreased upon cycling and after the 200th cycle the cell was able to cycle for more than 500 cycles without further fading.     

Two-Machine Stochastic Flow Shops With Blocking and the Traveling Salesman Problem

The paper deals with the problem of minimizing the expected makespan in a two-machine flow shop with blocking and random job processing times. It is well known that it reduces to an instance of the traveling salesman problem (TSP). Assuming that the job processing times can be stochastically ordered on both machines, we show that the problem under study is equivalent to TSP on a permuted Monge matrix. This allows us to prove that it is NP-hard for the independently and exponentially distributed job processing times, and identify a new class of efficiently solvable special cases.     

Risk assessment for a video surveillance system based on Fuzzy Cognitive Maps

For various IT systems security is considered a key quality factor. In particular, it might be crucial for video surveillance systems, as their goal is to provide continuous protection of critical infrastructure and other facilities. Risk assessment is an important activity in security management; it aims at identifying assets, threats and vulnerabilities, analysis of implemented countermeasures and their effectiveness in mitigating risks. This paper discusses an application of a new risk assessment method, in which risk calculation is based on Fuzzy Cognitive Maps (FCMs) to a complex automated video surveillance system. FCMs are used to capture dependencies between assets and FCM based reasoning is applied to aggregate risks assigned to lower-level assets (e.g. cameras, hardware, software modules, communications, people) to such high level assets as services, maintained data and processes. Lessons learned indicate, that the proposed method is an efficient and low-cost approach, giving instantaneous feedback and enabling reasoning on effectiveness of security system.     

Improved Accuracy of High-Order WENO Finite Volume Methods on Cartesian Grids

We propose a simple modification of standard weighted essentially non-oscillatory (WENO) finite volume methods for Cartesian grids, which retains the full spatial order of accuracy of the one-dimensional discretization when applied to nonlinear multidimensional systems of conservation laws. We derive formulas, which allow us to compute high-order accurate point values of the conserved quantities at grid cell interfaces. Using those point values, we can compute a high-order flux at the center of a grid cell interface. Finally, we use those point values to compute high-order accurate averaged fluxes at cell interfaces as needed by a finite volume method. The method is described in detail for the two-dimensional Euler equations of gas dynamics. An extension to the three-dimensional case as well as to other nonlinear systems of conservation laws in divergence form is straightforward. Furthermore, similar ideas can be used to improve the accuracy of WENO type methods for hyperbolic systems which are not in divergence form. Several test computations confirm the high-order accuracy for smooth nonlinear problems.     

Experiences with large-scale operational trials of ALTO-enhanced P2P filesharing in an intra-ISP scenario

Application Layer Traffic Optimization (ALTO) has recently gained attention in the research and standardisation community as a way for a network operator to guide the peer selection process of distributed applications by providing network layer topology information. In particular P2P applications are expected to gain from ALTO, due to the many connections peers form among each other, often without taking network layer topology information into account. In this paper, we present results of an extensive intra-ISP trial with an ALTO-enhanced P2P filesharing software. In summary, our results show that—depending on the concrete setting and on the distribution of upload capacity in the network—ALTO enables an ISP to save operational costs significantly while not degrading application layer performance noticeably. In addition, based on our experience we are able to give advice to operators on how to save costs with ALTO while not sacrificing application layer performance at all.     

State-space approach to nonlinear predictive generalised minimum variance control

A nonlinear predictive generalised minimum variance control algorithm is introduced for the control of nonlinear discrete-time multivariable systems. The plant model is represented by the combination of a very general nonlinear operator and also a linear subsystem which can be open-loop unstable and is represented in state-space model form. The multi-step predictive control cost index to be minimised involves both weighted error and control signal costing terms. The solution for the control law is derived in the time domain using a general operator representation of the process. The controller includes an internal model of the nonlinear process, but because of the assumed structure of the system, the state observer is only required to be linear. In the asymptotic case, where the plant is linear, the controller reduces to a state-space version of the well-known GPC controller.     

Characterization of Combinatorially Independent Permutation Separability Criteria

The so-called permutation separability criteria are simple operational conditions that are necessary for separability of mixed states of multipartite systems: (1) permute the indices of the density matrix and (2) check if the trace norm of at least one of the resulting operators is greater than one. If it is greater than one then the state is necessarily entangled. A shortcoming of the permutation separability criteria is that many permutations give rise to equivalent separability criteria. Therefore, we introduce a necessary condition for two permutations to yield independent criteria called combinatorial independence. This condition basically means that the map corresponding to one permutation cannot be obtained by concatenating the map corresponding to the second permutation with a norm-preserving map. We characterize completely combina-torially independent criteria, and determine simple permutations that represent all independent criteria. The representatives can be visualized by means of a simple graphical notation. They are composed of three basic operations: partial transpose, and two types of so-called reshufflings. In particular, for a four-partite system all criteria except one are composed of partial transpose and only one type of reshuffling; the exceptional one requires the second type of reshuffling. Furthermore, we show how to obtain efficiently a simple representative for every permutation. This method allows to check easily if two permutations are Combinatorially equivalent or not.