Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer.

The therapeutic effectiveness of oncolytic viruses (OVs) delivered intravenously is limited by the development of neutralizing antibody responses against the virus. To circumvent this limitation and to enable repeated systemic administration of OVs, here we develop Synthetic RNA viruses consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21, we demonstrate vRNA delivery and replication, virus assembly, spread and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promotes immune cell infiltration, remodeling of the tumor microenvironment, and enhances the activity of anti-PD-1 checkpoint inhibitor. In mouse and non-human primates, Synthetic-SVV is well tolerated reaching exposure well above the requirement for anti-tumor activity. Altogether, the Synthetic RNA virus platform provides an approach that enables repeat intravenous administration of viral immunotherapy.

Effect of the look-up line on the gaze and head orientation of elite ice hockey players.

A "look-up line" (LUL) has been proposed for ice hockey, which is an orange 1 m (40') warning line (WL) painted on the ice at the base of the boards. The LUL purports to provide an early warning to players to keep their head up prior to and as they are being checked. We determined if players looked up more on a rink with the LUL compared to a traditional Control rink. Elite offensive (O) and defensive (D) players competed 1 vs. 1, while wearing an eye tracker that recorded their quiet eye (QE) and fixation and tracking (F-T) and an electrogoniometer that measured head angle. External cameras recorded skate duration during four skate phases: P1 preparation, P2 decision-making, P3 cut to boards, P4 contact. The QE was the final fixation prior to contact between O and D as they skated towards and across the WL during P3 and P4. Skate phase durations (%) did not differ by rink or rink by position. More QE and F-T occurred on the WL on the LUL rink than on the Control. The expected increase in head angle on the LUL rink did not occur during P3 or P4. Post-hoc results also showed O and D skated further from the boards on the LUL rink, suggesting the players preferred to control the puck on white ice, rather than the orange colour of the LUL rink. More research is needed to determine if these results apply to the competitive setting.

Mechanism of the down regulation of photosynthesis by blue light in the Cyanobacterium synechocystis sp. PCC 6803.

Exposure to blue light has previously been shown to induce the reversible quenching of fluorescence in cyanobacteria, indicative of a photoprotective mechanism responsible for the down regulation of photosynthesis. We have investigated the molecular mechanism behind fluorescence quenching by characterizing changes in excitation energy transfer through the phycobilin pigments of the phycobilisome to chlorophyll with steady-state and time-resolved fluorescence excitation and emission spectroscopy. Quenching was investigated in both a photosystem II-less mutant, and DCMU-poisoned wild-type Synechocystis sp. PCC 6803. The action spectra for blue-light-induced quenching was identical in both cell types and was dominated by a band in the blue region, peaking at 480 nm. Fluorescence quenching and its dark recovery was inhibited by the protein cross-linking agent glutaraldehyde, which could maintain cells in either the quenched or the unquenched state. We found that high phosphate concentrations that inhibit phycobilisome mobility and the regulation of energy transfer by the light-state transition did not affect blue-light-induced fluorescence quenching. Both room temperature and 77 K fluorescence emission spectra revealed that fluorescence quenching was associated with phycobilin emission. Quenching was characterized by a decrease in the emission of allophycocyanin and long wavelength phycobilisome terminal emitters relative to that of phycocyanin. A global analysis of the room-temperature fluorescence decay kinetics revealed that phycocyanin and photosystem I decay components were unaffected by quenching, whereas the decay components originating from allophycocyanin and phycobilisome terminal emitters were altered. Our data support a regulatory mechanism involving a protein conformational change and/or change in protein-protein interaction which quenches excitation energy at the core of the phycobilisome.