Exosomes are cell-derived nanovesicles that hold promise as living vehicles for intracellular delivery of therapeutics to mammalian cells. This potential, however, is undermined by the lack of effective methods to load exosomes with therapeutic proteins and to facilitate their uptake by target cells. Here, we demonstrate how a vesicular stomatitis virus glycoprotein (VSVG) can both load protein cargo onto exosomes and increase their delivery ability via a pseudotyping mechanism. By fusing a set of fluorescent and luminescent reporters with VSVG, we show the successful targeting and incorporation of VSVG fusions into exosomes by gene transfection and fluorescence tracking. We subsequently validate our system by live cell imaging of VSVG and its participation in endosomes/exosomes that are ultimately released from transfected HEK293 cells. We show that VSVG pseudotyping of exosomes does not affect the size or distributions of the exosomes, and both the full-length VSVG and the VSVG without the ectodomain are shown to integrate into the exosomal membrane, suggesting that the ectodomain is not required for protein loading. Finally, exosomes pseudotyped with full-length VSVG are internalized by multiple-recipient cell types to a greater degree compared to exosomes loaded with VSVG without the ectodomain, confirming a role of the ectodomain in cell tropism. In summary, our work introduces a new genetically encoded pseudotyping platform to load and enhance the intracellular delivery of therapeutic proteins via exosome-based vehicles to target cells.
We study synchronization of two eccentric rotors (ERs) with common rotational axis in the vibration system of the far-resonant spatial motion. We deduce the dimensionless coupling equation of two ERs with applying the average method of small parameters. We convert the synchronization problem into the existence and stability of solving the zero solutions for the dimensionless coupling equations. By introducing the synchronization torque and the difference between the residual torques of two motors, we obtain the synchronization condition that two ERs achieve the synchronized motion. We derive the stability condition of the synchronized motion, which satisfies Routh-Hurwitz criterion. We discuss numerically the choosing motion feature of the vibration system, which indicates that the vibration system has two steady motion modes. The synchronization torque forces the phase difference to approachπwhen the structural parameters of the vibration system satisfy the condition of the spatial cone motion, and the synchronization torque drives the phase difference to approach zero when those satisfy the condition of the spatial circle motion. Finally, through the comparison and analysis of experimental data, the structural parameters of the vibration system satisfying the above two conditions can guarantee the synchronization stability for two ERs.
The integration of satellite and terrestrial 5G networks aims to provide ubiquitous coverage, improve service reliability, and enable the network scalability. However, the inherent characteristics of satellite channels bring challenges on the air interface design of integrated terrestrial-satellite networks. For example, for low earth orbits (LEO) mobile satellite communication (SatCom) system, it is unclear so far whether the 5G new radio (5G-NR) synchronization signals could meet the requirement of timing and frequency offset estimation in the presence of large Doppler shifts. In this paper, we investigate time and frequency synchronization for the downlink transmission of 5G-NR signals over LEO satellite channels. Starting from the maximum log-likelihood criterion for timing offset estimation given the observation of the received primary synchronization signals (PSS), we derive an upper bound of the objective function for simplicity. With a priori information that the maximum Doppler shift of LEO satellite-ground link is within a specific range, we construct the local synchronization sequence via using the modulated discrete prolate spheroidal sequences (DPSS) vectors. Then the timing offset estimation can be recast into a one-dimensional peak search problem. Moreover, the cyclic prefix (CP) structure of orthogonal frequency division multiplexing (OFDM) can be utilized to improve the estimation performance further. Once the timing and frequency offset are captured in the above initial synchronization phase, the tracking synchronization can be much simplified as the variation of both the timing and frequency offset is very small between two adjacent synchronization blocks. Simulation results show that by using the proposed algorithms, the 5G-NR signals can achieve near optimal downlink time and frequency synchronization in typical LEO SatCom systems.INDEX TERMS LEO satellite, 5G integrated network, time and frequency synchronization, Doppler shift.WENJIN WANG (M'14) received the Ph.D. degree in communication and information sys-
In vivo levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are critical to many physiological and pathological processes. Because of the distinct differences in their biological generation and effects, simultaneously visualizing both of them could help deepen our insights into the mechanistic details of these processes. However, real-time and deep-tissue imaging and differentiation of ROS-and RNS-related molecular events in living subjects still remain a challenge. Here, we report the development of two activatable 19 F magnetic resonance imaging (MRI) molecular probes with different 19 F chemical shifts and specific responsive behaviors for simultaneous in vivo detection and deep-tissue imaging of O 2•− and ONOO − . These probes are capable of real-time visualization and differentiation of O 2•− and ONOO − in living mice with drug-induced acute kidney injury by interference-free multiplexed hot-spot 19 F MRI, illustrating the potential of this technique for background-free real-time imaging of diverse biological processes, accurate diagnosis of various diseases in deep tissues, and rapid toxicity evaluation of assorted drugs.
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