Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma.

BACKGROUND: In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244. METHODS: To directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments. RESULTS: CD244fl/flLysMcre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244fl/flLysMcre mice also showed higher percentages of Ly6Clow macrophages, along with elevated gp100+IFN-γ+ CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6Clow macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244-/- bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. CONCLUSION: Our study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients.

Responsive parental support buffers the link between chronic stress and cardiometabolic risk among adolescents.

Youth exposed to chronic stress exhibit increased cardiometabolic risk which parental social support may attenuate. Notably, theories emphasize that support should be delivered responsively for it to exert buffering effects, but this has not been thoroughly tested empirically. This study examined whether timing of support is an important but unrecognized element of responsiveness during adolescence in buffering the link between chronic stress and cardiometabolic risk. Participants were 242 adolescents aged 15 years (63 % female, 38 % Black). Adolescents completed assessments of chronic stress (Life Stress Interview), and trained personnel collected anthropometric measures and blood samples to assess cardiometabolic risk (reflected in low-grade inflammation and metabolic syndrome). Adolescents also completed an eight-day diary assessment to report daily stressor exposure and parental support. Using the diary data, responsiveness of parental support was operationalized as the within-individual difference in parental support received on stressor (vs. non-stressor) days, such that increased parental support on stressor days reflected more timely support. Results suggest that responsive parental support buffered the link between chronic stress and cardiovascular risk. Specifically, chronic stress was associated with greater risk only when parental support was not temporally aligned with stress exposure, but this association was not observed among adolescents who received timely parental support. These findings shed light on why parental support may not always exert buffering effects during adolescence, highlighting the importance of taking a developmental approach to understanding protective effects.

Femtosecond-resolution optical pulse interleaving time error detector.

Pulse repetition rate multiplier (PRRM) is an essential component of microwave photonics systems, designed not only to alleviate photodiode saturation but also to provide more frequent pulses. However, the presence of interleaving time errors is known to compromise the advantages of PRRM. In this study, we present a high-sensitivity detection method for identifying these time errors using an electro-optic sampling-based timing detector (EOS-TD). We utilize two EOS-TDs: one for generating precise timing ruler signals and the other as a high-precision timing detector. In comparison to the conventional power ratio comparison method, our approach demonstrates sensitivity improvement by two orders of magnitude. This enhancement facilitates the measurement of femtosecond-level time errors. By enabling higher pulse rates while maintaining the ultralow jitter, this method can be useful for building higher-speed photonic systems.

Frozen Clay Minerals as a Potential Source of Bioavailable Iron and Magnetite.

Iron (Fe) is an essential micronutrient that affects biological production. Iron-containing clay minerals are an important source of bioavailable iron. However, the dissolution of iron-containing clay minerals at temperatures below the freezing point has not been investigated. Here, we demonstrate the enhanced reductive dissolution of iron from a clay mineral in ice in the presence of iodide (I-) as the electron donor. The accelerated production of dissolved iron in the frozen state was irreversible, and the freeze concentration effect was considered the main driving force. Furthermore, the formation of magnetite (Fe3O4) after the freezing process was observed using transmission electron microscopy analysis. Our results suggest a new mechanism of accelerated abiotic reduction of Fe(III) in clay minerals, which may release bioavailable iron, Fe(II), and reactive iodine species into the natural environment. We also propose a novel process for magnetite formation in ice. The freezing process can serve as a source of bioavailable iron or act as a sink, leading to the formation of magnetite.

Production of Molecular Iodine via a Redox Reaction between Iodate and Organic Compounds in Ice.

The abiotic mechanism of molecular iodine (I2) production from iodate (IO3-) remains largely unknown. Here, we demonstrate the production of I2 in the presence of IO3- and organic compounds in ice. When the solution containing IO3- (100 µM) and furfuryl alcohol (100 µM) at pH 3.0 was frozen at -20 °C, 13.1 µM of I2 was produced with complete degradation of furfuryl alcohol after 20 min. However, there was little change in the IO3- and furfuryl alcohol concentrations in water at 25 °C. The production of I2 in ice is due to the freeze concentration effect, which induces the accumulation of IO3-, furfuryl alcohol, and protons in the ice grain boundaries. This behavior facilitated the production of I2 via a redox reaction between IO3- and organic compounds. The production of I2 increased with increasing furfuryl alcohol concentration and decreasing pH. However, freezing temperature had a minor effect on the maximum production of I2. The production of I2 is highly dependent on the type of organic compounds. It was higher for organic compounds with higher electron-donating properties. This study suggests a new mechanism for I2 production, which is helpful for predicting precisely the atmospheric I2 budget in cold regions.

Synthesis of α-Branched Enones via Chloroacylation of Terminal Alkenes.

Here, we show the conversion of unactivated alkenes into α-branched enones via regioselective chloroacylation with acyl chlorides. The method relies upon the initial in situ generation of chlorine radicals directly from the acyl chloride precursor under cooperative nickel/photoredox catalysis. Subsequent HCl elimination provides enones and α,ß-unsaturated esters that are not accessible via the conventional acylation approaches that provide the other, linear constitutional isomer.

Frozen Hydrogen Peroxide and Nitrite Solution: The Acceleration of Benzoic Acid Oxidation via the Decreased pH in Ice.

We investigated benzoic acid oxidation via the reaction of hydrogen peroxide (H2O2) and nitrite (NO2-). The oxidation of benzoic acid by reactive nitrous acid (HONO) was negligible, and the reactivity of the H2O2/NO2- system decreased with a decrease in temperature under aqueous conditions. However, freezing markedly accelerated the chemical reaction. Based on Raman microscope measurements, concentrated species were confirmed in certain regions of the ice. We proposed that the change in nitrite speciation (accordingly, a decrease in the pH below pKa), derived from the freezing concentration effect, was the reason for the accelerated reactions. The oxidation characteristics of the system were monitored under varying conditions, such as initial pH, dosage ratio, benzoic acid concentration, and reaction with various benzene derivatives. The ultrahigh-performance liquid chromatography/electrospray ionization/mass spectrometry (UHPLC/ESI/MS) measurement showed that peroxynitrous acid (HOONO)-mediated oxidation generated hydroxylated and nitrated byproducts. Additionally, decarboxylated products were detected, indicating direct electron transfer from the organic compounds to HOONO. As freezing is a global phenomenon, and H2O2 and NO2- are ubiquitous in the environment, the transformation of aromatic compounds with H2O2/NO2- in cold environments must be considered in environmental chemistry.

Highly Bright Silica-Coated InP/ZnS Quantum Dot-Embedded Silica Nanoparticles as Biocompatible Nanoprobes.

Quantum dots (QDs) have outstanding optical properties such as strong fluorescence, excellent photostability, broad absorption spectra, and narrow emission bands, which make them useful for bioimaging. However, cadmium (Cd)-based QDs, which have been widely studied, have potential toxicity problems. Cd-free QDs have also been studied, but their weak photoluminescence (PL) intensity makes their practical use in bioimaging challenging. In this study, Cd-free QD nanoprobes for bioimaging were fabricated by densely embedding multiple indium phosphide/zinc sulfide (InP/ZnS) QDs onto silica templates and coating them with a silica shell. The fabricated silica-coated InP/ZnS QD-embedded silica nanoparticles (SiO2@InP QDs@SiO2 NPs) exhibited hydrophilic properties because of the surface silica shell. The quantum yield (QY), maximum emission peak wavelength, and full-width half-maximum (FWHM) of the final fabricated SiO2@InP QDs@SiO2 NPs were 6.61%, 527.01 nm, and 44.62 nm, respectively. Moreover, the brightness of the particles could be easily controlled by adjusting the amount of InP/ZnS QDs in the SiO2@InP QDs@SiO2 NPs. When SiO2@InP QDs@SiO2 NPs were administered to tumor syngeneic mice, the fluorescence signal was prominently detected in the tumor because of the preferential distribution of the SiO2@InP QDs@SiO2 NPs, demonstrating their applicability in bioimaging with NPs. Thus, SiO2@InP QDs@SiO2 NPs have the potential to successfully replace Cd-based QDs as highly bright and biocompatible fluorescent nanoprobes.

Self-stabilized soliton generation in a microresonator through mode-pulled Brillouin lasing.

Reducing the complexity required for starting and maintaining a soliton state has been a major task to fully miniaturize soliton microcombs including the accompanying external operating systems. Here we experimentally examine the generative process of a self-stabilized soliton in which a continuous-wave pump detuned on the thermally stable blue side of a resonance generates a Brillouin lasing signal that relays the pump power to the soliton pulses via intracavity mode-coupling without breaking thermal self-stability. Based on a simple setup consisting of a free-running laser and a microcavity without any external feedback systems by virtue of internal thermal locking, single-soliton pulses of 11 GHz repetition rate were deterministically generated. We demonstrate that the single-soliton pulses can be passively maintained over several days in a laboratory environment with a phase noise performance of -137dBc/Hz at 100 kHz.

Accelerated chromate reduction by tea waste: Comparison of chromate reduction properties between water and ice systems.

The concentration of chromium (Cr) in natural water and soil environments has gradually increased in recent decades, owing to intensive use of Cr in industry and its subsequent disposal. In this study, we performed a comparison study on chromate (Cr6+) reduction by tea waste (green tea, black tea, red tea, and chamomile) in water (25 °C) and ice (-20 °C) to develop a new strategy for environmental-friendly stabilization of hazardous Cr6+ by freezing. This study shows that the freezing process can enhance the reduction of Cr6+ by tea waste. The residual Cr6+ concentration ratios (C/C0, where C is the concentration of Cr6+ after the reaction (5 h) and C0 is the initial concentration of Cr6+ (20 µM) in the system) by tea wastes in water were in the range of 0.71 (green tea) to 0.92 (chamomile); however, the ratios dramatically decreased under the freezing process (i.e., 0.06 by green tea, 0.13 by black tea, 0.18 by red tea, and 0.08 by chamomile). According to the results obtained from the fluorescent, chromatographic, and spectroscopic analyses, under the freezing process, the enhanced reduction of Cr6+ could be explained by the freeze concentration of Cr6+, phenolic components in tea extracts, and protons in small liquid pockets in liquid-like layers (LLLs). In addition, the proposed system can efficiently purify the real Cr6+-containing wastewater (i.e., electroplating wastewater), indicating that the system will be economically feasible in cold regions (i.e., polar regions).

Au-Ag assembled on silica nanoprobes for visual semiquantitative detection of prostate-specific antigen.

BACKGROUND: Blood prostate-specific antigen (PSA) levels are widely used as diagnostic biomarkers for prostate cancer. Lateral-flow immunoassay (LFIA)-based PSA detection can overcome the limitations associated with other methods. LFIAbased PSA detection in clinical samples enables prognosis and early diagnosis owing to the use of high-performance signal reporters. RESULTS: Here, a semiquantitative LFIA platform for PSA detection in blood was developed using Au-Ag nanoparticles (NPs) assembled on silica NPs (SiO2@Au-Ag NPs) that served as signal reporters. Synthesized SiO2@Au-Ag NPs exhibited a high absorbance at a wide wavelength range (400-800 nm), with a high scattering on nitrocellulose membrane test strips. In LFIA, the color intensity of the test line on the test strip differed depending on the PSA concentration (0.30-10.00 ng/mL), and bands for the test line on the test strip could be used as a standard. When clinical samples were assessed using this LFIA, a visual test line with particular color intensity observed on the test strip enabled the early diagnosis and prognosis of patients with prostate cancer based on PSA detection. In addition, the relative standard deviation of reproducibility was 1.41%, indicating high reproducibility, and the signal reporter showed good stability for 10 days. CONCLUSION: These characteristics of the signal reporter demonstrated the reliability of the LFIA platform for PSA detection, suggesting potential applications in clinical sample analysis.

Inhibition of SARS-CoV-2 Virus Entry by the Crude Polysaccharides of Seaweeds and Abalone Viscera In Vitro.

Much attention is being devoted to the potential of marine sulfated polysaccharides as antiviral agents in preventing COVID-19. In this study, sulfated fucoidan and crude polysaccharides, extracted from six seaweed species (Undaria pinnatifida sporophyll, Laminaria japonica, Hizikia fusiforme, Sargassum horneri, Codium fragile, Porphyra tenera) and Haliotis discus hannai (abalone viscera), were screened for their inhibitory activity against SARS-CoV-2 virus entry. Most of them showed significant antiviral activities at an IC50 of 12~289 µg/mL against SARS-CoV-2 pseudovirus in HEK293/ACE2, except for P. tenera (IC50 > 1000 µg/mL). The crude polysaccharide of S. horneri showed the strongest antiviral activity, with an IC50 of 12 µg/mL, to prevent COVID-19 entry, and abalone viscera and H. fusiforme could also inhibit SARS-CoV-2 infection with an IC50 of 33 µg/mL and 47 µg/mL, respectively. The common properties of these crude polysaccharides, which have strong antiviral activity, are high molecular weight (>800 kDa), high total carbohydrate (62.7~99.1%), high fucose content (37.3~66.2%), and highly branched polysaccharides. These results indicated that the crude polysaccharides from seaweeds and abalone viscera can effectively inhibit SARS-CoV-2 entry.

Reductive transformation of hexavalent chromium by ferrous ions in a frozen environment: Mechanism, kinetics, and environmental implications.

The transformation between hexavalent chromium (Cr6+) and trivalent chromium (Cr3+) has a significant impact on ecosystems, as Cr6+ has higher levels of toxicity than Cr3+. In this regard, a variety of Cr6+ reduction processes occurring in natural environments have been studied extensively. In this work, we investigate the reductive transformation of Cr6+ by ferrous ions (Fe2+) in ice at -20 °C, and compare the same process in water at 25 °C. The Fe2+-mediated reduction of Cr6+ occurred much faster in ice than it did in water. The accelerated reduction of Cr6+ in ice is primarily ascribed to the accumulation of Cr6+, Fe2+, and protons in the grain boundaries formed during freezing, which constitutes favorable conditions for redox reactions between Cr6+ and Fe2+. This freeze concentration phenomenon was verified using UV-visible spectroscopy with o-cresolsulfonephthalein (as a pH indicator) and confocal Raman spectroscopy. The reductive transformation of Cr6+ (20 µM) by Fe2+ in ice proceeded rapidly under various Fe2+ concentrations (20-140 µM), pH values (2.0-5.0), and freezing temperatures (-10 to -30 °C) with a constant molar ratio of oxidized Fe2+ to reduced Cr6+ (3:1). This result implies that the proposed mechanism (i.e., the redox reaction between Cr6+ and Fe2+ in ice) can significantly contribute to the natural conversion of Cr6+ in cold regions. The Fe2+-mediated Cr6+ reduction kinetics in frozen Cr6+-contaminated wastewater was similar to that in frozen Cr6+ solution. This indicates that the variety of substrates typically present in electroplating wastewater have a negligible effect on the redox reaction between Cr6+ and Fe2+ in ice; it also proposes that the Fe2+/freezing process can be used for the treatment of Cr6+-contaminated wastewater.

Silver-Assembled Silica Nanoparticles in Lateral Flow Immunoassay for Visual Inspection of Prostate-Specific Antigen.

Prostate-specific antigen (PSA) is the best-known biomarker for early diagnosis of prostate cancer. For prostate cancer in particular, the threshold level of PSA <4.0 ng/mL in clinical samples is an important indicator. Quick and easy visual detection of the PSA level greatly helps in early detection and treatment of prostate cancer and reducing mortality. In this study, we developed optimized silica-coated silver-assembled silica nanoparticles (SiO2@Ag@SiO2 NPs) that were applied to a visual lateral flow immunoassay (LFIA) platform for PSA detection. During synthesis, the ratio of silica NPs to silver nitrate changed, and as the synthesized NPs exhibited distinct UV spectra and colors, most optimized SiO2@Ag@SiO2 NPs showed the potential for early prostate cancer diagnosis. The PSA detection limit of our LFIA platform was 1.1 ng/mL. By applying each SiO2@Ag@SiO2 NP to the visual LFIA platform, optimized SiO2@Ag@SiO2 NPs were selected in the test strip, and clinical samples from prostate cancer patients were successfully detected as the boundaries of non-specific binding were clearly seen and the level of PSA was <4 ng/mL, thus providing an avenue for quick prostate cancer diagnosis and early treatment.

Antiviral Activity of Two Marine Carotenoids against SARS-CoV-2 Virus Entry In Silico and In Vitro.

The marine carotenoids fucoxanthin and siphonaxanthin are powerful antioxidants that are attracting focused attention to identify a variety of health benefits and industry applications. In this study, the binding energy of these carotenoids with the SARS-CoV-2 Spike-glycoprotein was predicted by molecular docking simulation, and their inhibitory activity was confirmed with SARS-CoV-2 pseudovirus on HEK293 cells overexpressing angiotensin-converting enzyme 2 (ACE2). Siphonaxanthin from Codium fragile showed significant antiviral activity with an IC50 of 87.4 µM against SARS-CoV-2 pseudovirus entry, while fucoxanthin from Undaria pinnatifida sporophyll did not. The acute toxicities were predicted to be relatively low, and pharmacokinetic predictions indicate GI absorption. Although further studies are needed to elucidate the inhibition of viral infection by siphonaxanthin, these results provide useful information in the application of these marine carotenoids for the treatment and prevention of COVID-19.

Wikstroemiaganpi Extract Improved Atopic Dermatitis-Like Skin Lesions via Suppression of Interleukin-4 in 2,4-Dinitrochlorobenzene-Induced SKH-1 Hairless Mice.

Plants of the genus Wikstroemia are used in Chinese traditional medicine to treat inflammatory diseases, such as arthritis, bronchitis, and pneumonia. The present study was designed to determine whether Wikstroemia ganpi (Siebold and Zucc.) Maxim. offers a potential means of treating 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) in mice. Symptoms such as redness, edema, and keratinization in AD mice induced by DNCB were alleviated by the co-application of an ethanolic extract of W. ganpi for 2 weeks. The severity of skin barrier function damage was evaluated by measuring TEWL (transepidermal water loss). TEWLs of DNCB sensitized mouse dorsal skin were reduced by the application of a W. ganpi ethanolic extract, and skin hydration was increased. In addition, the infiltration of inflammatory cells into the dermis was significantly reduced, as were blood levels of IgE and IL-4, which play an important role in the expression of AD. The results of this experiment suggest that W. ganpi is a potential therapeutic agent for AD.

Optical frequency comb noise spectra analysis using an asymmetric fiber delay line interferometer.

A simple and practical apparatus enabling repetition rate (frep) noise, carrier-envelope frequency (fceo) noise and nth optical comb mode (νn) noise spectra measurements with high precision is established. The frep and νn noise spectra are measured by a fiber delay line interferometer, while fceo noise spectrum is measured by an f-2f interferometer. We utilize this apparatus to characterize the noise performance of an Er-fiber optical frequency comb (OFC) and analyze the origin of dominant noise sources. Moreover, this apparatus provides a powerful tool for diagnosing noise dynamics intrinsic in mode-locked lasers and OFCs. To this end, we uncover the anti-correlation between frep and fceo noise as well as the impact of servo loops on noise characteristics in the stabilized OFC.

Femtosecond synchronization of multiple mode-locked lasers and a microwave oscillator by multicolor electro-optic sampling.

Simple multicolor electro-optic sampling-based femtosecond synchronization of multiple mode-locked lasers is demonstrated. Parallel timing error detection between each laser and a common microwave is achieved by wavelength division multiplexing and demultiplexing. The parallel timing error detection enables simultaneous femtosecond synchronization of more than two mode-locked lasers to the microwave oscillator, even when the lasers have different repetition rates. The residual root-mean-square (rms) timing jitter of laser-laser synchronization measured by an optical cross correlator is 2.6 fs (integration bandwidth, 100 Hz-1 MHz), which is limited by the actuator bandwidth in the laser oscillator. The long-term rms timing drift and frequency instability of laser-microwave synchronization are 7.1 fs (over 10,000 s) and 5.5×10-18 (over 2000 s averaging time), respectively. As a versatile and reconfigurable tool for laser-laser and laser-microwave synchronization, the demonstrated method can be used for various applications ranging from ultrafast x-ray and electron science facilities to dual- and triple-comb spectroscopy.

Photonic Flywheel in a Monolithic Fiber Resonator.

We demonstrate the first compact photonic flywheel with sub-fs time jitter (averaging times up to 10 µs) at the quantum-noise limit of a monolithic fiber resonator. Such quantum-limited performance is accessed through novel two-step pumping scheme for dissipative Kerr soliton generation. Controllable interaction between stimulated Brillouin lasing and Kerr nonlinearity enhances the DKS coherence and mitigates the thermal instability challenge, achieving a remarkable 22-Hz intrinsic comb linewidth and an unprecedented phase noise of -180 dBc/Hz at 945-MHz carrier at free running. The scheme can be generalized to various device platforms for field-deployable precision metrology.

Freezing-Induced Simultaneous Reduction of Chromate and Production of Molecular Iodine: Mechanism, Kinetics, and Practical Implications.

A new method for the concurrent treatment of Cr(VI)-contaminated wastewater and production of the useful I2 chemical was developed. The method is based on the redox reaction between Cr(VI) and I- that occurs when an aqueous wastewater solution containing Cr(VI) and I- is frozen, producing I2 and allowing for the effective removal of Cr. The redox reaction occurs primarily because of the accumulation of Cr(VI), I-, and protons in the ice grain boundaries formed during freezing (i.e., the freeze concentration effect). This effect was verified by confocal Raman spectroscopy and the experiments varying I- concentration and pH. The reduction of Cr(VI) (20 µM) was near complete after freezing at I- concentrations ≥ 100 µM, pH ≤ 3.0, and temperatures ≤ -10 °C. The freezing method (liquid cooling vs air cooling) had little effect on the final Cr(VI) reduction efficiency but had a significant effect on the Cr(VI) reduction rate. The freezing method was also tested with Cr(VI)-contaminated electroplating wastewater samples, and simultaneous Cr(VI) reduction and I2 production proceeded rapidly in a frozen solution but was not observed in an aqueous solution. Additionally, other substances in electroplating wastewater did not reduce the rate and final efficiency of Cr(VI) reduction and I2 production. Therefore, the freezing/Cr(VI)/I- system can be considered a feasible approach to water-energy nexus technology for simultaneous I2 production and Cr(VI)-contaminated wastewater treatment.