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BackgroundIn situ vaccination (ISV) is a cancer immunotherapy strategy in which immunostimulatory reagents are introduced directly into a tumor to stimulate antitumor immunity both against the treated tumor and systemically against untreated tumors. Recently, we showed that cowpea mosaic virus (CPMV) is a potent multi-toll-like receptor (TLR) agonist with potent efficacy for treating tumors in mice and dogs by ISV. However, ISV with CPMV alone does not uniformly treat all mouse tumor models tested, however this can be overcome through strategic combinations. More insight is needed to delineate potency and mechanism of systemic antitumor immunity and abscopal effect.MethodWe investigated the systemic efficacy (abscopal effect) of CPMV ISV with a two-tumor mouse model using murine tumor lines B16F10, 4T1, CT26 and MC38. Flow cytometry identified changes in cell populations responsible for systemic efficacy of CPMV. Transgenic knockout mice and depleting antibodies validated the role of relevant candidate cell populations and cytokines. We evaluated these findings and engineered a multicomponent combination therapy to specifically target the candidate cell population and investigated its systemic efficacy, acquired resistance and immunological memory in mouse models.ResultsISV with CPMV induces systemic antitumor T-cell-mediated immunity that inhibits growth of untreated tumors and requires conventional type-1 dendritic cells (cDC1s). Furthermore, using multiple tumor mouse models resistant to anti-programmed death 1 (PD-1) therapy, we tested the hypothesis that CPMV along with local activation of antigen-presenting cells with agonistic anti-CD40 can synergize and strengthen antitumor efficacy. Indeed, this combination ISV strategy induces an influx of CD8+ T cells, triggers regression in both treated local and untreated distant tumors and potentiates tumor responses to anti-PD-1 therapy. Moreover, serial ISV overcomes resistance to anti-PD-1 therapy and establishes tumor-specific immunological memory.ConclusionsThese findings provide new insights into in situ TLR activation and cDC1 recruitment as effective strategies to overcome resistance to immunotherapy in treated and untreated tumors.

This document is a correction notice for an article titled "AI is a viable alternative to high throughput screening: a 318-target study" published in Scientific Reports. The correction includes updates to the list of authors and their affiliations, as well as corrections to the affiliation information for certain authors. Additionally, an outdated version of Figure 1 was included in the original article, and the Acknowledgements section contained an error. The original article has been corrected to address these issues. [Extracted from the article]

The allyl-alkenyl-norbornenyl polycyclization, which is energetically viable, is used for forming the longifolene core. It is found out that the cation-alkene interaction is actually enhanced by the presence of the alkyl tether.

The first-principles prediction of dislocation nucleation in metallic systems subject to realistically sized indenters requires a multiscale approach due to the prohibitive computational expense. The largest empirical atomistic simulations include at most a billion atoms, at the same time requiring the parameterization of new interactions whenever an additional species or crystal structure is added. The multiscale orbital-free density functional theory–local quasicontinuum (OFDFT-LQC) method overcomes these problems by using first-principles OFDFT to capture the atomic interactions while relying upon LQC to evolve the macroscopic system. We use this method to indent the (111) surface of a 2×2×1μm piece of L1 2   Al 3 Mg. Using a localization criterion, the first dislocation is predicted to form off-axis on the slip plane in the direction after the indenter has penetrated 70  nm. Other popular dislocation nucleation criteria give different predictions. These results are strikingly similar to those for indentation into the (111) surface of Al, indicating that the underlying crystal structure, not the atomic identity, is the most important factor in determining the onset of plasticity. [ABSTRACT FROM AUTHOR]

Langmuir-Blodgett monolayers of a donor-acceptor diad TTF-sigma-(trinitrofluorene) (8) with an extremely low HOMO-LUMO gap (0.3 eV) have been used to create molecular junction devices that show rectification behavior. By virtue of structural similarities and position of molecular orbitals, 8 is the closest well-studied analogue of the model Aviram-Ratner unimolecular rectifier (TTF-sigma-TCNQ). Compressing the monolayer results in aligning the molecules, and is followed by a drastic increase in the rectification ratio. The direction of rectification depends on the electrodes used and is different in n-Si/8/Ti and Au/8/C16H33S-Hg junctions. The molecular nature of such behavior was corroborated by control experiments with fatty acids and by reversing the rectification direction with changing the molecular orientation (Au/D-sigma-A versus Au/A-sigma-D).