Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Genome-wide CRISPR screening identifies the pivotal role of ANKRD42 in colorectal cancer metastasis through EMT regulation.

Colorectal cancer (CRC), a pervasive and lethal malignancy of gastrointestinal cancer, imposes significant challenges due to the occurrence of distant metastasis in advanced stages. Understanding the intricate regulatory mechanisms driving CRC distant metastasis is of paramount importance. CRISPR-Cas9 screening has emerged as a powerful tool for investigating tumor initiation and progression. However, its application in studying CRC distant metastasis remains largely unexplored. To establish a model that faithfully recapitulates CRC liver metastasis in patients, we developed an in vivo genome-wide CRISPR-Cas9 screening approach using a spleen-injected liver metastasis mouse model. Through comprehensive screening of a whole-genome sgRNA library, we identified ANKRD42 as a pivotal regulatory gene facilitating CRC liver metastasis. Analysis of the TCGA database and our clinical cohorts unveiled heightened ANKRD42 expression in metastases. At the cellular level, the attenuation of ANKRD42 impaired the migration and invasion processes of tumor cells. In vivo experiments further validated these observations, highlighting the diminished liver metastatic capacity of tumor cells upon ANKRD42 knockdown. To unravel the specific mechanisms by which ANKRD42 regulates CRC distant metastasis, we leveraged patient-derived organoid (PDO) models. Depleting ANKRD42 in PDOs sourced from liver metastases precipitated the downregulation of pivotal genes linked to epithelial-mesenchymal transition (EMT), including CDH2 and SNAI2, thereby effectively suppressing tumor metastasis. This study not only establishes a conceptual framework but also identifies potential therapeutic avenues for advanced-stage distant metastasis in CRC patients.

DHM/SERS reveals cellular morphology and molecular changes during iPSCs-derived activation of astrocytes.

The activation of astrocytes derived from induced pluripotent stem cells (iPSCs) is of great significance in neuroscience research, and it is crucial to obtain both cellular morphology and biomolecular information non-destructively in situ, which is still complicated by the traditional optical microscopy and biochemical methods such as immunofluorescence and western blot. In this study, we combined digital holographic microscopy (DHM) and surface-enhanced Raman scattering (SERS) to investigate the activation characteristics of iPSCs-derived astrocytes. It was found that the projected area of activated astrocytes decreased by 67%, while the cell dry mass increased by 23%, and the cells changed from a flat polygonal shape to an elongated star-shaped morphology. SERS analysis further revealed an increase in the intensities of protein spectral peaks (phenylalanine 1001 cm-1, proline 1043 cm-1, etc.) and lipid-related peaks (phosphatidylserine 524 cm-1, triglycerides 1264 cm-1, etc.) decreased in intensity. Principal component analysis-linear discriminant analysis (PCA-LDA) modeling based on spectral data distinguished resting and reactive astrocytes with a high accuracy of 96.5%. The increase in dry mass correlated with the increase in protein content, while the decrease in projected area indicated the adjustment of lipid composition and cell membrane remodeling. Importantly, the results not only reveal the cellular morphology and molecular changes during iPSCs-derived astrocytes activation but also reflect their mapping relationship, thereby providing new insights into diagnosing and treating neurodegenerative diseases.

Convenient dual-wavelength digital holography based on orthogonal polarization strategy with a Wollaston prism.

Dual-wavelength digital holography effectively expands the measurement range of digital holography, but it increases the complexity of optical system due to non-common-path of two wavelengths. Here, by using orthogonal polarization strategy, we present a dual-wavelength digital holography based on a Wollaston prism (DWDH-WP) to separate the reference beams of two wavelengths and realize the common-path of two wavelengths. A Wollaston prism is inset into the reference beam path of the off-axis digital holography system, so two orthogonal-polarized reference beams of two different wavelengths separated at different directions are generated. Then a dual-wavelength multiplexed interferogram with orthogonal interference fringes is captured by using a monochrome camera, in which both the polarization orientations and the interference fringe orientations of two wavelengths are orthogonal, so the spectral crosstalk of two wavelengths with arbitrary wavelength difference can be avoided. Compared with the existing DWDH method, the proposed DWDH-WP method can conveniently realize the common-path of the reference beams of two wavelengths, so it reveals obvious advantages in spectral separation, spectral crosstalk, system simplification, and adjustment flexibility. Both effectiveness and flexibility of the proposed DWDH-WP method are demonstrated by the phase measurement of the HeLa cell and vortex phase plate.

Adaptive phase-shifting interferometry based on a phase-shifting digital holography algorithm.

Phase-shifting interferometry (PSI) requires accurate phase shifts between interferograms for realizing high-accuracy phase retrieval. This paper presents an adaptive PSI through synchronously capturing phase shifts measurement interferograms and phase measurement interferograms, in which the former is a series of spatial carrier frequency phase-shifting interferograms generated by an additional assembly and the phase shifts are calculated with the single-spectrum phase shifts measurement algorithm (SS-PSMA), the latter is employed for phase retrieval with an adaptive phase-shifting digital holography algorithm (PSDHA) based on complex amplitude recovery. In addition to exhibiting excellent reliability, high-accuracy phase retrieval (0.02 rad), and short calculation time (<25 ms), the proposed adaptive PSDHA is suitable for various interferograms with different fringe shapes and numbers. Importantly, both simulation analysis and experimental result demonstrate that this adaptive PSI based on PSDHA can effectively eliminate phase-shifting errors caused by phase shifter and external disturbance, ensuring high-accuracy phase shifts measurement and phase retrieval, meanwhile significantly reducing phase-shifting interferograms acquisition time and phase retrieval calculation time.

Specific lineage transition of tumor-associated macrophages elicits immune evasion of ascitic tumor cells in gastric cancer with peritoneal metastasis.

BACKGROUND: Gastric cancer with peritoneal metastasis (PM-GC), recognized as one of the deadliest cancers. However, whether and how the tumor cell-extrinsic tumor microenvironment (TME) is involved in the therapeutic failure remains unknown. Thus, this study systematically assessed the immunosuppressive tumor microenvironment in ascites from patients with PM-GC, and its contribution to dissemination and immune evasion of ascites-disseminated tumor cells (aDTCs). METHODS: Sixty-three ascites and 43 peripheral blood (PB) samples from 51 patients with PM-GC were included in this study. aDTCs in ascites and circulating tumor cells (CTCs) in paired PB were immunophenotypically profiled. Using single-cell RNA transcriptional sequencing (scRNA-seq), crosstalk between aDTCs and the TME features of ascites was inspected. Further studies on the mechanism underlying aDTCs-immune cells crosstalk were performed on in vitro cultured aDTCs. RESULTS: Immune cells in ascites interact with aDTCs, prompting their immune evasion. Specifically, we found that the tumor-associated macrophages (TAMs) in ascites underwent a continuum lineage transition from cathepsinhigh (CTShigh) to complement 1qhigh (C1Qhigh) TAM. CTShigh TAM initially attracted the metastatic tumor cells to ascites, thereafter, transitioning terminally to C1Qhigh TAM to trigger overproliferation and immune escape of aDTCs. Mechanistically, we demonstrated that C1Qhigh TAMs significantly enhanced the expression of PD-L1 and NECTIN2 on aDTCs, which was driven by the activation of the C1q-mediated complement pathway. CONCLUSIONS: For the first time, we identified an immunosuppressive macrophage transition from CTShigh to C1Qhigh TAM in ascites from patients with PM-GC. This may contribute to developing potential TAM-targeted immunotherapies for PM-GC.

Influential upregulation of KCNE4: Propelling cancer associated fibroblasts-driven colorectal cancer progression.

BACKGROUND: Colorectal cancer (CRC) is a malignancy of remarkable heterogeneity and heightened morbidity. Cancer associated fibroblasts (CAFs) are abundant in CRC tissues and are essential for CRC growth. Here, we aimed to develop a CAF-related classifier for predicting the prognosis of CRC and identify critical pro-tumorigenic genes in CAFs. METHOD: The mRNA expression and clinical information of CRC samples were sourced from two comprehensive databases, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Using a weighted gene co-expression network analysis (WGCNA) approach, CAF-related genes were identified and a CAF risk signature was developed through the application of univariate analysis and the least absolute shrinkage and selection operator (LASSO) Cox regression model. EdU cell proliferation assay, and transwell assay were performed to detect the oncogenic role of KCNE4 in CAFs. RESULTS: We constructed a prognostic CAF model consisting of two genes (SFRP2 and KCNE4). CRC patients were classified into low- and high-CAF-risk groups using the median CAF risk score, and patients in the high-CAF-risk group had worse prognosis. Meanwhile, a higher risk score for CAFs was associated with greater stromal and CAF infiltrations, as well as higher expression of CAF markers. Furthermore, TIDE analysis indicated that patients with a high CAF risk score are less responsive to immunotherapy. Our further experiments had confirmed the strong correlation between KCNE4 and the malignant phenotypes of CAFs. Moreover, we had shown that KCNE4 could actively promote tumor-promoting phenotypes in CAFs, indicating its critical role in cancer progression. CONCLUSION: The two-gene prognostic CAF signature was constructed and could be reliable for predicting prognosis for CRC patients. Moreover, KCNE4 may be a promising strategy for the development of novel anti-cancer therapeutics specifically directed against CAFs.

Claudin-18.2 mediated interaction of gastric Cancer cells and Cancer-associated fibroblasts drives tumor progression.

BACKGROUND: Claudin-18.2 (CLDN18.2) has emerged as an alluring therapeutic target against gastrointestinal tumors in recent years. However, a thorough understanding of its regulatory mechanism in gastric cancer remains elusive. METHODS: We presented a comprehensive study comprising 185 gastric cancer patients, which included 112 cases with high CLDN18.2 expression and 73 cases with low CLDN18.2 expression as determined by immunohistochemistry. After overdressed CLDN18.2 in AGS and NUGC4 cell lines, we elucidated the functions of CLDN18.2 in connecting gastric cancer cells and cancer-associated fibroblasts (CAFs) through an in vitro adhesion models and in vivo lung colonization models. The molecular mechanism underlying CLDN18.2-mediated interaction between gastric cancer cells and CAFs was identified through RNA sequencing and protein-proximity labeling techniques in vivo. RESULTS: In our own cohort, a correlation was observed between high levels of CLDN18.2 expression and advanced cancer stage, poor prognosis, and heightened infiltration of CAFs. We elucidated a pivotal role of CLDN18.2 in mediating adhesion between gastric cancer cells and CAFs, which leads to the adhesion of cancer cells to stroma tissue and facilitates the clustering of cancer cells and CAFs into embolus, enhancing gastric cancer's metastatic progression and the risk of embolic death. Mechanistically, it was discovered that CAFs can activate adhesion and metastasis-related signaling pathways in CLDN18.2-positive gastric cancer cells. Furthermore, using an in vivo protein-proximity labeling approach, we identified S100 calcium binding protein A4 (S100A4) as a distinctive marker of CAFs that interacts with CLDN18.2 to enhance gastric cancer progression. CONCLUSIONS: Our findings illuminated the role of the CLDN18.2-mediated interaction between cancer cells and CAFs in promoting gastric cancer progression and embolism, thereby providing insight into potential therapeutic avenues for CLDN18.2 positive cancers. Video Abstract.

The tumor immune microenvironment remodeling and response to HER2-targeted therapy in HER2-positive advanced gastric cancer.

Combination therapy with anti-HER2 agents and immunotherapy has demonstrated significant clinical benefits in gastric cancer (GC), but the underlying mechanism remains unclear. In this study, we used multiplex immunohistochemistry to assess the changes of the tumor microenvironment in 47 advanced GC patients receiving anti-HER2 therapy. Additionally, we performed single-cell transcriptional sequencing to investigate potential cell-to-cell communication and molecular mechanisms in four HER2-positive GC baseline samples. We observed that post-treated the infiltration of NK cells, CD8+ T cells, and B lymphocytes were significantly higher in patients who benefited from anti-HER2 treatment than baseline. Further spatial distribution analysis demonstrated that the interaction scores between NK cells and CD8+ T cells, B lymphocytes and M2 macrophages, B lymphocytes and Tregs were also significantly higher in benefited patients. Cell-cell communication analysis from scRNA sequencing showed that NK cells utilized CCL3/CCL4-CCR5 to recruit CD8+ T cell infiltration. B lymphocytes employed CD74-APP/COPA/MIF to interact with M2 macrophages, and utilized TNF-FAS/ICOS/TNFRSR1B to interact with Tregs. These cell-cell interactions contribute to inhibit the immune resistance of M2 macrophages and Tregs. Our research provides potential guidance for the use of anti-HER2 therapy in combination with immune therapy.

Deubiquitinase OTUD6A Regulates Innate Immune Response via Targeting UBC13.

OTUD6A is a deubiquitinase that plays crucial roles in various human diseases. However, the precise regulatory mechanism of OTUD6A remains unclear. In this study, we found that OTUD6A significantly inhibited the production of type I interferon. Consistently, peritoneal macrophages and bone marrow-derived macrophages from Otud6a-/- mice produced more type I interferon after virus infection compared to cells from WT mice. Otud6a-/-- mice also exhibited increased resistance to lethal HSV-1 and VSV infections, as well as LPS attacks due to decreased inflammatory responses. Mechanistically, mass spectrometry results revealed that UBC13 was an OTUD6A-interacting protein, and the interaction was significantly enhanced after HSV-1 stimulation. Taken together, our findings suggest that OTUD6A plays a crucial role in the innate immune response and may serve as a potential therapeutic target for infectious disease.

Real-time phase imaging with physics-enhanced network and equivariance.

Learning-based phase imaging balances high fidelity and speed. However, supervised training requires unmistakable and large-scale datasets, which are often hard or impossible to obtain. Here, we propose an architecture for real-time phase imaging based on physics-enhanced network and equivariance (PEPI). The measurement consistency and equivariant consistency of physical diffraction images are used to optimize the network parameters and invert the process from a single diffraction pattern. In addition, we propose a regularization method based total variation kernel (TV-K) function constraint to output more texture details and high-frequency information. The results show that PEPI can produce the object phase quickly and accurately, and the proposed learning strategy performs closely to the fully supervised method in the evaluation function. Moreover, the PEPI solution can handle high-frequency details better than the fully supervised method. The reconstruction results validate the robustness and generalization ability of the proposed method. Specially, our results show that PEPI leads to considerable performance improvement on the imaging inverse problem, thereby paving the way for high-precision unsupervised phase imaging.

γδ T cells recruitment and local proliferation in brain parenchyma benefit anti-neuroinflammation after cerebral microbleeds.

Background: Cerebral microbleeds (CMBs) are an early sign of many neurological disorders and accompanied by local neuroinflammation and brain damage. As important regulators of immune response and neuroinflammation, the biological behavior and role of γδ T cells after CMBs remain largely unknown. Methods: We made a spot injury of microvessel in the somatosensory cortex to mimic the model of CMBs by two-photon laser and in vivo tracked dynamical behaviors of γδ T cells induced by CMBs using TCR-δGFP transgenic mice. Biological features of γδ T cells in the peri-CMBs parenchyma were decoded by flow cytometry and Raman spectra. In wildtype and γδ T cell-deficient mice, neuroinflammation and neurite degeneration in the peri-CMBs cortex were studied by RNAseq, immunostaining and in vivo imaging respectively. Results: After CMBs, γδ T cells in the dural vessels were tracked to cross the meningeal structure and invade the brain parenchyma in a few days, where the division process of γδ T cells were captured. Parenchymal γδ T cells were highly expressed by CXCR6 and CCR6, similar to meningeal γδ T cells, positive for IL-17A and Ki67 (more than 98%), and they contained abundant substances for energy metabolism and nucleic acid synthesis. In γδ T cell-deficient mice, cortical samples showed the upregulation of neuroinflammatory signaling pathways, enhanced glial response and M1 microglial polarization, and earlier neuronal degeneration in the peri-CMBs brain parenchyma compared with wildtype mice. Conclusion: CMBs induce the accumulation and local proliferation of γδ T cells in the brain parenchyma, and γδ T cells exert anti-neuroinflammatory and neuroprotective effects at the early stage of CMBs.

A SERS-Based Dual-Parameter Monitoring Nanoprobe of ROS and PI3K/Akt during Ginsenoside Rg3-Induced Cell Apoptosis.

Both the reactive oxygen species (ROS) level and Phosphatidylinositol 3 Kinase (PI3K) protein content are two crucial parameters for characterizing states of cell apoptosis. Current methods measure these parameters with two different techniques, respectively, which usually lead to evaluation contingency. Ginsenoside Rg3 exhibits an excellent anticancer effect, which is enacted by the Phosphatidylinositol 3 Kinase/Protein Kinase B (PI3K/Akt) pathway involving ROS; however, the precise mechanism that induces cell apoptosis remains unknown. This is due to the lack of information on quantitative intracellular ROS and PI3K. Here, we used a surface-enhanced Raman scattering (SERS)-based boric acid nanoprobe to monitor the intracellular ROS level and phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3) content, which reflects the regulatory effect of the PI3K/Akt pathway. After treatment with ginsenoside Rg3, the PI3K/Akt content first increased and then decreased as the ROS level increased. Moreover, when the ROS level significantly increased, the mitochondrial membrane potential reduced, thus indicating the dynamic regulation effect of intracellular ROS level on the PI3K/Akt pathway. Importantly, in addition to avoiding evaluation contingency, which is caused by measuring the aforementioned parameters with two different techniques, this SERS-based dual-parameter monitoring nanoprobe provides an effective solution for simultaneous ROS level and PI3K content measurements during cell apoptosis. Furthermore, the intracellular ROS level was also able to have a dynamic regulatory effect on the PI3K/Akt pathway, which is essential for studying ROS/PI3K/Akt-pathway-related cell apoptosis and its activation mechanism.

The collateral activity of RfxCas13d can induce lethality in a RfxCas13d knock-in mouse model.

BACKGROUND: The CRISPR-Cas13 system is an RNA-guided RNA-targeting system and has been widely used in transcriptome engineering with potentially important clinical applications. However, it is still controversial whether Cas13 exhibits collateral activity in mammalian cells. RESULTS: Here, we find that knocking down gene expression using RfxCas13d in the adult brain neurons caused death of mice, which may result from the collateral activity of RfxCas13d rather than the loss of target gene function or off-target effects. Mechanistically, we show that RfxCas13d exhibits collateral activity in mammalian cells, which is positively correlated with the abundance of target RNA. The collateral activity of RfxCas13d could cleave 28s rRNA into two fragments, leading to translation attenuation and activation of the ZAKα-JNK/p38-immediate early gene pathway. CONCLUSIONS: These findings provide new mechanistic insights into the collateral activity of RfxCas13d in mammalian cells and warn that the biosafety of the CRISPR-Cas13 system needs further evaluation before application to clinical treatments.

Reconfigurable Radiation Angle Continuous Deflection of All-Dielectric Phase-Change V-Shaped Antenna.

All-dielectric optical antenna with multiple Mie modes and lower inherent ohmic loss can achieve high efficiency of light manipulation. However, the silicon-based optical antenna is not reconfigurable for specific scenarios. The refractive index of optical phase-change materials can be reconfigured under stimulus, and this singular behavior makes it a good candidate for making reconfigurable passive optical devices. Here, the optical radiation characteristics of the V-shaped phase-change antenna are investigated theoretically. The results show that with increasing crystallinity, the maximum radiation direction of the V-shaped phase-change antenna can be continuously deflected by 90°. The exact multipole decomposition analysis reveals that the modulus and interference phase difference of the main multipole moments change with the crystallinity, resulting in a continuous deflection of the maximum radiation direction. Thus, the power ratio in the two vertical radiation directions can be monotonically reversed from -12 to 7 dB between 20% and 80% crystallinity. The V-shaped phase-change antenna exhibits the potential to act as the basic structural unit to construct a reconfigurable passive spatial angular power splitter or wavelength multiplexer. The mechanism analysis of radiation directivity involving the modulus and interference phase difference of the multipole moments will provide a reference for the design and optimization of the phase-change antenna.

SAFA facilitates chromatin opening of immune genes through interacting with anti-viral host RNAs.

Regulation of chromatin structure and accessibility determines the transcription activities of genes, which endows the host with function-specific patterns of gene expression. Upon viral infection, the innate immune responses provide the first line of defense, allowing rapid production of variegated antiviral cytokines. Knowledge on how chromatin accessibility is regulated during host defense against viral infection remains limited. Our previous work found that the nuclear matrix protein SAFA surveilled viral RNA and regulated antiviral immune genes expression. However, how SAFA regulates the specific induction of antiviral immune genes remains unknown. Here, through integration of RNA-seq, ATAC-seq and ChIP-seq assays, we found that the depletion of SAFA specifically decreased the chromatin accessibility, activation and expression of virus induced genes. And mutation assays suggested that the RNA-binding ability of SAFA was essential for its function in regulating antiviral chromatin accessibility. RIP-seq results showed that SAFA exclusively bound with antiviral related RNAs following viral infection. Further, we combined the CRISPR-Cas13d mediated RNA knockdown system with ATAC-qPCR, and demonstrated that the binding between SAFA and according antiviral RNAs specifically mediated the openness of the corresponding chromatin and following robust transcription of antiviral genes. Moreover, knockdown of these associated RNAs dampened the accessibility of related genes in an extranuclear signaling pathway dependent manner. Interestingly, VSV infection cleaved SAFA protein at the C-terminus which deprived its RNA binding ability for immune evasion. Thus, our results demonstrated that SAFA and the interacting RNA products collaborated and remodeled chromatin accessibility to facilitate antiviral innate immune responses.

Colorimetry /SERS dual-sensor of H2O2 constructed via TMB-Fe3O4@ AuNPs.

Hydrogen peroxide (H2O2) detection with high sensitivity plays an important role in biomedical research and food engineering. By combining colorimetry and surface enhanced Raman spectroscopy (SERS), we synthetize a novel H2O2 dual-sensor constructed via TMB-Fe3O4@AuNPs. In the presence of H2O2, the peroxide model enzyme might catalyze the oxidation of 3,3',5,5'- tetramethylbenzidine (TMB) as blue charge transfer complex (CTC) for colorimetry, and then facilitate the sensitivity improvement of SERS detection. The achieved results show that in colorimetry, the linear range is from 40 µM to 5.5 mM with the detection limit of 11.1 µM; in SERS detection, the linear range is from 2 nM to 1 µM with the detection limit of 0.275 nM. Clearly, this mutual reference strategy improves both the detection limit of colorimetry and the sensitivity of SERS detection. Moreover, this colorimetry/SERS dual-sensor constructed via TMB-Fe3O4@AuNPs is successfully applied to the H2O2 detection in plasma and milk, indicating the excellent performance and flexibility.

Optical nanoantenna with muitiple surface plasmon resonances for enhancements in near-field intensity and far-field radiation.

Plasmonic nanostructures with dual surface plasmon resonances capable of simultaneously realizing strong light confinement and efficient light radiation are attractive for light-matter interaction and nanoscale optical detection. Here, we propose an optical nanoantenna by adding gold nanoring to the conventional Fano-type resonance antenna. With the help of gold nanoring, the following improvements are simultaneously realized: (1). The near-field intensity of the Fano-type antenna is further enhanced by the Fabry Perot-like resonance formed by the combination of the gold nanoring and the substrate waveguide layer. (2). Directional radiation is realized by the collaboration of the gold nanoring and the Fano-type antenna, thus improving the collection efficiency of the far-field signal. (3). The multi-wavelength tunable performance of the Fano resonance antenna is significantly improved by replacing the superradiation mode in the Fano resonance with the dipole resonance induced by the gold nanoring. The optical properties of the nanoantennas are demonstrated by numerical simulations and practical devices. Therefore, the proposed optical nanoantenna provides a new idea for further improving the performance of conventional Fano-type nanoantennas and opens new horizons for designing plasmonic devices with enhancements in both near- and far-field functionalities, which can be applied in a wide range of applications such as surface-enhanced spectroscopy, photoluminescence, nonlinear nanomaterials/emitters and biomedicine sensing.

Broadband Raman scattering enhancement with reduced heat generation in a dielectric-metal hybrid nanocavity.

The strongly localized electric field achieved in metallic nanoparticles (NPs) and nanostructures are commonly employed to realize surface-enhanced Raman scattering. However, the heat originating from the Ohmic loss of metals may lead to the damage of the analyzed molecules, which severely limits the practical applications of pure-metallic nanostructures. Here, we propose a dielectric-metallic hybrid nanocavity placing silicon (Si) NPs onto a gold (Au) film to realize broadband Raman scattering enhancement with significantly reduced heat generation. Our results reveal that the heat generation is dramatically reduced in the hybrid nanocavity as compared with its pure-metallic counterpart while a significantly enhanced electric field is maintained. We demonstrate numerically and experimentally that the optical resonances, which arise from the coherent coupling of the electric and magnetic dipoles excited inside the Si NP with their mirror images arisen from the Au film, can be employed to enhance the excitation and radiation of Raman signals, respectively. We find that the enhancement in the radiation of Raman signals plays a crucial role in enhancing the total Raman scattering. We also show that the hybrid nanocavity acts as a nano-antenna which effectively radiates Raman signals into the far-field. These findings indicate the advantages of such hybrid nanocavities in temperature-sensitive Raman scattering characterization and supply new strategies for designing nanoscale photonic devices of other functionalities with hybrid nanocavities.

Epigenetic regulation in antiviral innate immunity.

Emerging life-threatening viruses have posed great challenges to public health. It is now increasingly clear that epigenetics plays a role in shaping host-virus interactions and there is a great need for a more thorough understanding of these intricate interactions through the epigenetic lens, which may represent potential therapeutic opportunities in the clinic. In this review, we highlight the current understanding of the roles of key epigenetic regulators - chromatin remodeling and histone modification - in modulating chromatin openness during host defense against virus. We also discuss how the RNA modification m6A (N6-methyladenosine) affects fundamental aspects of host-virus interactions. We conclude with future directions for uncovering more detailed functions that epigenetic regulation exerts on both host cells and viruses during infection.