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The mammalian reovirus Type 3 Dearing (T3D) is a naturally occurring oncolytic virus. We previously identified a T3D variant isolated from persistently infected cancer cells that has a premature stop codon mutation in the S1 gene, generating a truncated σ1-attachment protein that lacks the globular head. We now report on the molecular characterization of this variant, named RP116, and assess its antitumor potential in human cancer cells and syngeneic mouse models. RP116 replicates efficiently in several cancer cell lines, shows reduced dependency for the JAM-A receptor, significantly decreases tumor growth in syngeneic models when injected either intratumorally or intravenously, and generates long-term cures and immune memory in combination with checkpoint inhibitors. Finally, we demonstrate that RP116 infection in mice leads to reduced production of neutralizing antibodies directed against reovirus T3D, preserving the efficacy of subsequent reovirus treatment. These results establish the value of developing RP116 as an additional oncolytic reovirus platform.

Background Transgenes deliver therapeutic payloads to improve oncolytic virus immunotherapy. Transgenes encoded within oncolytic viruses are designed to be highly transcribed, but protein synthesis is often negatively affected by viral infection, compromising the amount of therapeutic protein expressed. Studying the oncolytic herpes simplex virus-1 (HSV1), we found standard transgene mRNAs to be suboptimally translated in infected cells.Methods Using RNA-Seq reads, we determined the transcription start sites and 5'leaders of HSV1 genes and uncovered the US11 5'leader to confer superior activity in translation reporter assays. We then incorporated this 5’leader into GM-CSF expression cassette in oncolytic HSV1 and compared the translationally adapted oncolytic virus with the conventional, leaderless, virus in vitro and in mice.Results Inclusion of the US11 5’leader in the GM-CSF transgene incorporated into HSV1 boosted translation in vitro and in vivo. Importantly, treatment with US11 5’leader-GM-CSF oncolytic HSV1 showed superior antitumor immune activity and improved survival in a syngeneic mouse model of colorectal cancer as compared with leaderless-GM-CSF HSV1.Conclusions Our study demonstrates the therapeutic value of identifying and integrating platform-specific cis-acting sequences that confer increased protein synthesis on transgene expression.

Abstract Although increasing evidence has confirmed that the apoptosis of renal tubular epithelial cells (RTECs) is a crucial contributor to the onset and development of septic acute kidney injury (AKI), the pathological mechanism by which RTEC apoptosis is upregulated during septic AKI is not entirely clear. In this study, a rat model of septic AKI was induced by a cecal ligation puncture procedure or lipopolysaccharide (LPS) injection. Four differentially expressed long noncoding RNAs (DE-Lncs) in the rat model of septic AKI were determined using RNA-sequencing and verified by qRT-PCR. Among the four DE-Lncs, the expression level of lncRNA NONRATG019935.2 (9935) exhibited the most significant reduction in both septic AKI rats and LPS-treated NRK-52E cells (a rat RTEC line). The overexpression of 9935 suppressed cell apoptosis and p53 protein level in LPS-treated NRK-52E cells, and retarded septic AKI development in the rat model of septic AKI. Mechanistically, 9935 decreased the human antigen R (HuR)-mediated Tp53 mRNA stability by limiting the combination of HuR and the 3′UTR region of Tp53 mRNA in RTECs. The overexpression of HuR abrogated the inhibitory effect of pcDNA-9935 on the LPS-induced apoptosis of NRK-52E and rat primary RTECs. In conclusion, 9935 exerts its role in septic AKI by suppressing the p53-mediated apoptosis of RTECs, and this essential role of 9935 relies on its destructive effect on HuR-mediated Tp53 mRNA stability.

Modern handheld mobile devices are equipped with a complementary metal-oxide-semiconductor (CMOS) image sensor. These image sensors are capable of perceiving intensity changes in optically modulated signals, driving the rapid development of optical camera communication (OCC). In this study, direct-current offset orthogonal frequency division multiplexing (DCO-OFDM) was developed for a rolling shutter OCC system in order to improve the data transmission rates of OCC systems. Two DCO-OFDM OCC signal detection algorithms, namely the parabolic column vector selection (P-CVS) algorithm and the decomposition of extremely low frequency component (D-ELFC) algorithm, were proposed, along with a frequency-domain downsampling scheme, to eliminate the influence from both the blooming effect and shot noise. The experimental results, obtained after using a self-built DCO-OFDM OCC testbed with a general commercial smartphone camera, demonstrated that the D-ELFC algorithm outperformed in the bit error rate (BER) in comparison to the P-CVS algorithm and achieved a data transmission rate >22 kbps under the conditions of the BER being below the 20% forward error correction (FEC) limit and the illuminance being higher than 510 lux.

In the last few years, optical camera communication (OCC) has benefited from built-in CMOS image sensors in smart devices. OCC is now considered a candidate for incorporation into IEEE 802.15.7r1. A major study on OCC was conducted for line-of-sight (LOS) environments. To enable users to receive OCC signals reflected from any surface easily, we considered non-LOS (NLOS) OCC in a heterogeneous reflective background in this study. A modified background subtraction method was proposed to identify the transmitted modulated signal that was recorded in an image. Then, the majority vote principle was used to restore the damaged pixels that were primarily caused by nonuniform reflection from the heterogeneous reflective background. The experimental results obtained after using a self-built NLOS OCC system demonstrated a significant improvement in the bit error rate when the proposed OCC signal recovery method was used for different distances between a smartphone and a heterogeneous reflective background.

Recent studies of the northeastern part of the Tibetan Plateau have called attention to two emerging views of how the Tibetan Plateau has grown. First, deformation in northern Tibet began essentially at the time of collision with India, not 10-20 Myr later as might be expected if the locus of activity migrated northward as India penetrated the rest of Eurasia. Thus, the north-south dimensions of the Tibetan Plateau were set mainly by differences in lithospheric strength, with strong lithosphere beneath India and the Tarim and Qaidam basins steadily encroaching on one another as the region between them, the present-day Tibetan Plateau, deformed, and its north-south dimension became narrower. Second, abundant evidence calls for acceleration of deformation, including the formation of new faults, in northeastern Tibet since ~15 Ma and a less precisely dated change in orientation of crustal shortening since ~20 Ma. This reorientation of crustal shortening and roughly concurrent outward growth of high terrain, which swings from NNE-SSW in northern Tibet to more NE-SW and even ENE-WSW in the easternmost part of northeastern Tibet, are likely to be, in part, a consequence of crustal thickening within the high Tibetan Plateau reaching a limit, and the locus of continued shortening then migrating to the northeastern and eastern flanks. These changes in rates and orientation also could result from removal of some or all mantle lithosphere and increased gravitational potential energy per unit area and from a weakening of crustal material so that it could flow in response to pressure gradients set by evolving differences in elevation. Key Points The north-south limits of Tibet were set by lateral variations in strength Roughly 15 million years ago, deformation of NE Tibet accelerated Since 20-15 million years ago, the orientation of shortening rotated eastward ©2013. American Geophysical Union. All Rights Reserved.

Traditional intravenous chemotherapy is relative to many systemic side effects, including myelosuppression, liver or kidney dysfunction, and neurotoxicity. As an alternative method, the injectable hydrogel can efficiently avoid these problems by releasing drugs topically at the tumor site. With advantages of localized drug toxicity in the tumor site, proper injectable hydrogel as the drug delivery system has become a research hotspot. Based on different types and stages of cancer, a variety of hydrogel drug delivery systems were developed, including thermosensitive, pH-sensitive, photosensitive, and dual-sensitive hydrogel. In this review, the latest developments of these hydrogels and related drug delivery systems were summarized. In summary, our increasing knowledge of injectable hydrogel for localized cancer therapy ensures us that it is a more durable and effective approach than traditional chemotherapy. Smart release system reacting to different stimuli at different time according to the micro-environment changes in the tumor site is a promising tendency for further studies.

The diffusion of polymer chains in a crowded environment with large and small immobile, attractive nanoparticles (NPs) is studied using Langevin dynamics simulations. For orderly distributed NPs on the simple cubic lattice, our results show that the diffusion of polymer chains is dependent on the NP–NP distance or lattice distance d. At low d where NPs are placed closely, subdiffusion occurs at a sufficiently high polydispersity of NPs, PD. Both the apparent diffusion coefficient and subdiffusion exponent of polymer chains decrease with increasing PD, attributed to the adsorption of polymers on NP clusters formed by larger NPs. At large d, normal diffusion is always observed, and the diffusion coefficient increases with increasing PD. The reason is that, at high PD, the difference between single large NP adsorption and double large NP adsorption is reduced, which increases the exchange of a polymer between the two adsorption states. Finally, the impact of size polydispersity of NPs on the diffusion of polymer chains in a crowded environment with randomly distributed NPs is also investigated. The results show that the position disorder of NPs enhances the subdiffusion of the system. [ABSTRACT FROM AUTHOR]