Anti-Tumor Immunogenicity of the Oncolytic Virus CF33-hNIS-antiPDL1 against Ex Vivo Peritoneal Cells from Gastric Cancer Patients.

We studied the immunotherapeutic potential of CF33-hNIS-antiPDL1 oncolytic virus (OV) against gastric cancer with peritoneal metastasis (GCPM). We collected fresh malignant ascites (MA) or peritoneal washings (PW) during routine paracenteses and diagnostic laparoscopies from GC patients (n = 27). Cells were analyzed for cancer cell markers and T cells, or treated with PBS, CF33-GFP, or CF33-hNIS-antiPDL1 (MOI = 3). We analyzed infectivity, replication, cytotoxicity, CD107α upregulation of CD8+ and CD4+ T cells, CD274 (PD-L1) blockade of cancer cells by virus-encoded anti-PD-L1 scFv, and the release of growth factors and cytokines. We observed higher CD45-/large-size cells and lower CD8+ T cell percentages in MA than PW. CD45-/large-size cells were morphologically malignant and expressed CD274 (PD-L1), CD252 (OX40L), and EGFR. CD4+ and CD8+ T cells did not express cell surface exhaustion markers. Virus infection and replication increased cancer cell death at 15 h and 48 h. CF33-hNIS-antiPDL1 treatment produced functional anti-PD-L1 scFv, which blocked surface PD-L1 binding of live cancer cells and increased CD8+CD107α+ and CD4+CD107α+ T cell percentages while decreasing EGF, PDGF, soluble anti-PD-L1, and IL-10. CF33-OVs infect, replicate in, express functional proteins, and kill ex vivo GCPM cells with immune-activating effects. CF33-hNIS-antiPDL1 displays real potential for intraperitoneal GCPM therapy.

Plug-and-play QKD architecture with a self-optical pulse train generator.

The commercialization of quantum key distribution (QKD), which enables secure communication even in the era of quantum computers, has acquired significant interest. In particular, plug-and-play (PnP) QKD has garnered considerable attention owing to its advantage in system stabilization. However, a PnP QKD system has limitations on miniaturization owing to a bulky storage line (SL) of tens of kilometers. And, the secure key rate is relatively low because Bob transmits the signal pulses only at the dedicated time slots to circumvent backscattering noise. This study proposes a new method that can eliminate the SL by realizing an optical pulse train generator based on an optical cavity structure. Our method allows Alice to generate optical pulse trains herself by duplicating Bob's seed pulse and excludes the need for Bob's strong signal pulses that trigger backscattering noise as much as the conventional PnP QKD. Accordingly, our method can naturally overcome the miniaturization limitation and the slow secure key rate, as the storage line is no longer necessary. We conducted a proof-of-concept experiment using our method and achieved a key generation rate of 1.6×10-3 count/pulse and quantum bit error rate ≤ 5%.

Simply structured polarization-independent high efficiency multilayer dielectric gratings.

A polarization-independent multilayer dielectric diffraction grating with a low aspect ratio and high diffraction efficiency was designed and fabricated. The diffraction grating designed with a grating density of 1200 lines/mm had an aspect ratio of 0.59, mean polarization-independent diffraction efficiency in the Littrow angle of ±2.5∘, and 1030-1080 nm wavelength range of 97.2%. The designed grating was fabricated using ion assisted deposition and reactive ion etching techniques. The mean polarization-independent diffraction efficiency of the fabricated grating was 96.1%, and its standard deviation was 0.68%. The fabricated diffraction grating was irradiated with a 1064 nm cw laser, with a power density of 30kW/cm2, for 1 min to measure the temperature change before and after the laser application. It was verified that the temperature variation of the diffraction grating without heat treatment was 8.8°C, and the temperature variation after heat treatment at 400°C decreased to 2.3°C.

ATAD5 restricts R-loop formation through PCNA unloading and RNA helicase maintenance at the replication fork.

R-loops are formed when replicative forks collide with the transcriptional machinery and can cause genomic instability. However, it is unclear how R-loops are regulated at transcription-replication conflict (TRC) sites and how replisome proteins are regulated to prevent R-loop formation or mediate R-loop tolerance. Here, we report that ATAD5, a PCNA unloader, plays dual functions to reduce R-loops both under normal and replication stress conditions. ATAD5 interacts with RNA helicases such as DDX1, DDX5, DDX21 and DHX9 and increases the abundance of these helicases at replication forks to facilitate R-loop resolution. Depletion of ATAD5 or ATAD5-interacting RNA helicases consistently increases R-loops during the S phase and reduces the replication rate, both of which are enhanced by replication stress. In addition to R-loop resolution, ATAD5 prevents the generation of new R-loops behind the replication forks by unloading PCNA which, otherwise, accumulates and persists on DNA, causing a collision with the transcription machinery. Depletion of ATAD5 reduces transcription rates due to PCNA accumulation. Consistent with the role of ATAD5 and RNA helicases in maintaining genomic integrity by regulating R-loops, the corresponding genes were mutated or downregulated in several human tumors.

Graphene perfect absorber design based on an approach of mimicking a one-port system in an asymmetric single resonator.

We proposed a novel perfect absorber with an asymmetric single resonator supporting two degenerate resonant modes, whose operation concept is mimicking a one-port system by making only one of the modes experience loss while using the other for an internal 100% reflector in conjunction with the background scattering. We confirmed the operation principle and the design requirement from a theoretical study using the temporal coupled-mode theory. We also designed an example device based on the guided-mode resonances (GMRs) in a slab-waveguide grating and numerically demonstrated a high absorption of ∼ 99.95% in monolayer graphene with greatly enhanced fabrication error tolerance in comparison to the previously proposed scheme. Our proposed scheme will find various useful applications due to the intuitive design process and relatively easier fabrication, which is attributed to the one-port mimicking operation concept with a single GMR-based broadband flat-top reflector.

Ultra-compact integrated terahertz modulator based on a graphene metasurface.

We propose a new type of a mid-infrared ultra-compact optical modulator composed of a graphene metasurface. Unlike the previously proposed schemes based on loss variation of materials or interference, the proposed one utilizes the unique topological characteristic of the isofrequency contour in the hyperbolic metasurface to modulate the transmission. The designed modulator provides a modulation depth of 10.7 dB, the length of which is 750 nm, corresponding to ∼1/30 of an operating wavelength.

Directional coupler design for orbital angular momentum mode-based photonic integrated circuits.

An orbital angular momentum (OAM) dividable on-chip directional coupler design is proposed. To guide OAM modes of topological charge number l = ±1, a waveguide needs to support TE01 and TE10 modes with degeneracy. When a directional coupler is made with such an OAM mode waveguide, it is additionally required to equalize the horizontal-direction coupling strengths of those two OAM constitutive eigenmodes. Base on the coupled mode theory formulation, we have found that this requirement can hardly be satisfied and devised a modified cross-shaped waveguide structure to solve this problem. An example design of OAM mode directional coupler is demonstrated. The coupling length of the designed device is 670 µm, and our numerical simulation showed negligible degradation of OAM mode purity during the operation of complete optical power transfer between two waveguides. To the best of our knowledge, this is the first proposal of the on-chip OAM mode directional coupler. The proposed design approach can be applied to implement various devices for OAM mode-based photonic integrated circuits.

Cross-cultural regularities in the cognitive architecture of pride.

Pride occurs in every known culture, appears early in development, is reliably triggered by achievements and formidability, and causes a characteristic display that is recognized everywhere. Here, we evaluate the theory that pride evolved to guide decisions relevant to pursuing actions that enhance valuation and respect for a person in the minds of others. By hypothesis, pride is a neurocomputational program tailored by selection to orchestrate cognition and behavior in the service of: (i) motivating the cost-effective pursuit of courses of action that would increase others' valuations and respect of the individual, (ii) motivating the advertisement of acts or characteristics whose recognition by others would lead them to enhance their evaluations of the individual, and (iii) mobilizing the individual to take advantage of the resulting enhanced social landscape. To modulate how much to invest in actions that might lead to enhanced evaluations by others, the pride system must forecast the magnitude of the evaluations the action would evoke in the audience and calibrate its activation proportionally. We tested this prediction in 16 countries across 4 continents (n = 2,085), for 25 acts and traits. As predicted, the pride intensity for a given act or trait closely tracks the valuations of audiences, local (mean r = +0.82) and foreign (mean r = +0.75). This relationship is specific to pride and does not generalize to other positive emotions that coactivate with pride but lack its audience-recalibrating function.

Vitamin D as a Primer for Oncolytic Viral Therapy in Colon Cancer Models.

Oncolytic viroimmunotherapy is an exciting modality that can offer lasting anti-tumor immunity for aggressive malignancies like colon cancer. The impact of oncolytic viruses may be extended by combining them with agents to prime a tumor for viral susceptibility. This study investigates vitamin D analogue as an adjunct to oncolytic viral therapy for colon cancer. While vitamin D (VD) has historically been viewed as anti-viral, our in vitro investigations using human colon cancer cell lines showed that VD does not directly inhibit replication of recombinant chimeric poxvirus CF33. VD did restrict growth in HT29 but not HCT116 human colon cancer cells. In vivo investigations using HCT116 and HT29 xenograft models of colon cancer demonstrated that a VD analogue, calcipotriol, was additive with CF33-based viral therapy in VD-responsive HT29 but not in HCT116 tumors. Analyses of RNA-sequencing and gene expression data demonstrated a downregulation in the Jak-STAT signaling pathway with the addition of VD to viral therapy in HT29 models suggesting that the anti-inflammatory properties of VD may enhance the effects of viral therapy in some models. In conclusion, VD may prime oncolytic viral therapy in certain colon cancers.

Molecular Design of Highly Efficient Heavy-Atom-Free Triplet BODIPY Derivatives for Photodynamic Therapy and Bioimaging.

Novel BODIPY photosensitizers were developed for imaging-guided photodynamic therapy. The introduction of a strong electron donor to the BODIPY core through a phenyl linker combined with the twisted arrangement between the donor and the BODIPY acceptor is essential for reducing the energy gap between the lowest singlet excited state and the lowest triplet state (ΔEST ), leading to a significant enhancement in the intersystem crossing (ISC) of the BODIPYs. Remarkably, the BDP-5 with the smallest ΔEST (ca. 0.44 eV) exhibited excellent singlet oxygen generation capabilities in both organic and aqueous solutions. BDP-5 also displayed bright emission in the far-red/near-infrared region in the condensed states. More importantly, both in vitro and in vivo studies demonstrated that BDP-5 NPs displayed a high potential for photodynamic cancer therapy and bioimaging.

An Emerging Molecular Design Approach to Heavy-Atom-Free Photosensitizers for Enhanced Photodynamic Therapy under Hypoxia.

A novel strategy for designing highly efficient and activatable photosensitizers that can effectively generate reactive oxygen species (ROS) under both normoxia and hypoxia is proposed. Replacing both oxygen atoms in conventional naphthalimides (RNI-O) with sulfur atoms led to dramatic changes in the photophysical properties. The remarkable fluorescence quenching (ΦPL ≈ 0) of the resulting thionaphthalimides (RNI-S) suggested that the intersystem crossing from the singlet excited state to the reactive triplet state was enhanced by the sulfur substitution. Surprisingly, the singlet oxygen quantum yield of RNI-S gradually increased with increasing electron-donating ability of the 4-R substituents (MANI-S, ΦΔ ≈ 1.00, in air-saturated acetonitrile). Theoretical studies revealed that small singlet-triplet energy gaps and large spin-orbit coupling could be responsible for the efficient population of the triplet state of RNI-S. In particular, the ROS generation ability of MANI-S was suppressed under physiological conditions due to their self-assembly and was significantly recovered in cancer cells. More importantly, cellular experiments showed that MANI-S still produced a considerable amount of ROS even under severely hypoxic conditions (1% O2) through a type-I mechanism.

Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal effect at a single low dose.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been increasing by 0.5% per year in the United States. PDAC portends a dismal prognosis and novel therapies are needed. This study describes the generation and characterization of a novel oncolytic chimeric orthopoxvirus for the treatment of pancreatic cancer. METHODS: After chimerization and high-throughput screening, CF33 was chosen from 100 new chimeric orthopoxvirus isolates for its ability to kill pancreatic cancer cells. In vitro cytotoxicity was assayed in six pancreatic cancer cell lines. In vivo efficacy and toxicity were evaluated in PANC-1 and MIA PaCa-2 xenograft models. RESULTS: CF33 caused rapid killing of six pancreatic cancer cells lines in vitro, releasing damage-associated molecular patterns, and regression of PANC-1 injected and non-injected distant xenografts in vivo after a single low intratumoral dose of 103 plaque-forming units. Using luciferase imaging, CF33 was noted to preferentially replicate in tumors which corresponds to the low viral titers found in solid organs. CONCLUSION: The low dose of CF33 required to treat pancreatic cancer in this preclinical study may ease the manufacturing and dosing challenges currently facing oncolytic viral therapy.

Optical bistability based on hyperbolic metamaterials.

We numerically demonstrate optical bistability in a nonlinear multilayer structure by utilizing the unique dispersion of hyperbolic metamaterials. The linear transmission is varied sharply with topological transition of isofrequency contour of the multilayer structure, and this non-resonant scheme enables realization of optical bistability with a short response time and a relatively low switching intensity. We have investigated exhaustively all possible topological transitions in the dispersion characteristics of the multilayer structure for optical bistability, and shown that the hyperbolic metamaterial (HMM) type transition from Type II to Type I, and the transition from Type II HMM to effective dielectric are suitable for realizing high-performances optical bistability. The proposed schemes can overcome the trade-off between a switching intensity and a response time in resonance based optical bistabilities.

Wavefront improvement in an end-pumped high-power Nd:YAG zigzag slab laser.

Techniques for wavefront improvement in an end-pumped Nd:YAG zigzag slab laser amplifier were proposed and demonstrated experimentally. First, a study on the contact materials was conducted to improve the heat transfer between the slab and cooling blocks and to increase the cooling uniformity. Among many attempts, only the use of silicon oil showed an improvement in the wavefront. Thus, the appropriate silicone oil was applied to the amplifier as a contact material. In addition, the wavefront compensation method using a glass rod array was also applied to the amplifier. A very low wavefront distortion was obtained through the use of a silicone-oil contact and glass rod array. The variance of the optical path difference for the entire beam height was 3.87 µm at a pump power of 10.6 kW, and that for the 80% section was 1.69 µm. The output power from the oscillator was 3.88 kW, which means the maximum output extracted from the amplifier at a pump power of 10.6 kW.

Ionic effects on the proton transfer mechanism in aqueous solutions.

Proton dissociation (PD) reactions of weak acids and proton transfer (PT) processes in aqueous solutions are strongly influenced by ions. However, a detailed molecular picture that describes how ions affect the rates of PD and PT processes is still missing. Here, we utilize time-resolved fluorescence spectroscopy combined with quantum chemical calculations to investigate the excited-state proton transfer (ESPT) reaction of a photoacid in aqueous metal chloride solutions. The activation energy (Ea) for the ESPT of the photoacid increases with increasing charge density of cations (ρcat). The local hydrogen bond (H-bond) structure of the photoacid in the ionic hydration shell is strongly related to both the Ea and the ρcat. Most importantly, the proton's positive charge in the transition state, which is delocalized through the H-bonded water channel, is more destabilized with an increase in the ρcat, leading to a higher Ea. Our experimental and computational results allow us to elucidate the underlying mechanism for the ionic effect on PD and the subsequent PT process at the molecular level.

Angle- and position-insensitive electrically tunable absorption in graphene by epsilon-near-zero effect.

We propose an electrically tunable absorber based on epsilon-near-zero (ENZ) effect of graphene embedded in a nanocavity, which is composed of metal grating and substrate. Due to strong surface-normal electric field confined in ENZ graphene in the proposed structure, greatly enhanced light absorption (~80%) is achieved in an ultrathin graphene monolayer. By electrically controlling the Fermi-level of graphene, a sharp peak absorption wavelength is tuned over a wide range. The proposed device can work as an optical modulator or a tunable absorption filter, which has a unique feature of incident angle insensitiveness owing to the ENZ effect and magnetic dipole resonance. Moreover, existence of a significantly dominant electric field and its uniformity make the device performance independent of the position of the graphene layer in the nanocavity, which provides great fabrication tolerance.

Optical reflection modulation using surface plasmon resonance in a graphene-embedded hybrid plasmonic waveguide at an optical communication wavelength.

We propose a high-performance, graphene-based optical modulator with a surface plasmon resonance (SPR) at 1550 nm. In the proposed device, a graphene layer is embedded in a hybrid plasmonic waveguide to enhance the light-graphene interaction. The adjustment of the permittivity of the graphene causes a significant modulation of the absorption in the SPR through a variation of the field confinement in the graphene layer, in addition to a resonant angle shift. With an optimal thickness of a metal (Ag) film and the properly chosen operation point of the Fermi level of graphene, a modulation depth of ∼100% was achieved. As the number of graphene layers in the proposed device increases, the insertion loss decreases. With five-layer graphene, a 6% insertion loss was achieved.

Slot-embedded photonic-crystal resonator with enhanced modal confinement.

A photonic-crystal (PC) resonator has attracted a great deal of attention for the strong light-matter interaction. Many attempts have been made to achieve a high-quality factor of the PC resonator, but they always have accompanied increases of modal volumes. In this work, we propose a novel method to enhance modal confinement of the PC resonator without compromising the quality factor. In the proposed structure, a thin low-index slot layer is embedded in a two-dimensional PC for vertical confinement, which results in a remarkable mode volume reduction without a decrease of the quality factor. By optimizing the slot thickness, a quality factor to mode volume ratio, which is a figure of merit for an optical resonator, could be increased by 8 times.

Dominant mode control of a graphene-embedded hybrid plasmonic resonator for a tunable nanolaser.

A graphene-embedded tunable plasmonic nanodisk resonator operating at near-infrared wavelength range is proposed, in which a certain resonant mode among multiple whispering-gallery modes (WGMs) can be selected as a dominant mode by modulating the Fermi level of the graphene. Our theoretical investigation reveals that the dominant mode selection mechanism in the proposed resonator is governed by the figure-of-merit (FOM) of the one-dimensional (1D) waveguide of the resonator's vertical structure, which is defined as a propagation length to mode size ratio. As the conductivity of the graphene changes with a gating voltage, the wavelength dependence of the FOM changes and a WGM closest to the maximum FOM wavelength is selected. Partial tuning of the selected dominant mode is incurred by the change of the effective index of the 1D waveguide. This novel mode selection mechanism of the proposed resonator can be adopted to realize an optically pumped tunable nanolaser with a wide wavelength tuning range.

Metal nanodisk hybrid plasmonic resonator on dielectric substrate for relieved fabrication complexity.

We propose a metal nanodisk hybrid plasmonic resonator (HPR), which consists of a metallic nanodisk on top of a dielectric slab. In contrast to the previously studied plasmonic resonator structures based on metal substrates such as the nanopatch resonator, the fabrication process of the proposed resonator is much easier because of a dielectric substrate. The performance of the proposed resonator has been theoretically investigated and compared to the previously studied structures. It has been shown that the performance of the proposed resonator is superior to that of the nanopatch resonator and comparable to that of a hybrid resonator based on a metal substrate.