Real-time tunable notched waveguide based on voltage controllable ferroelectric resonator.

In the present study, we have devised and conducted an investigation into a real-time tunable notched waveguide, employing a voltage-controllable plasmonic resonator. This plasmonic resonator is meticulously engineered from a ferroelectric substrate featuring a compound multilayer structure, thereby conferring it with the remarkable capability of flexible permittivity control. Furthermore, we have implemented two non-intersecting Archimedean spiral electrodes on the surface of the ferroelectric substrate, dedicated to applying the bias field onto the controllable plasmonic ferroelectric resonator (CPFR). Notably, our system affords the capability to finely tune both the magnetic and electric modes, achieving precise adjustments of 8.7% and 11%, respectively. The performance is complemented by minimal insertion loss, rapid response times, and a broad range of potential applications, positioning it as a candidate for a diverse array of notched waveguide scenarios.

Draining Lymph Node Metastasis Model for Assessing the Dynamics of Antigen-Specific CD8+ T Cells During Tumorigenesis.

Tumor antigen-specific CD8+ T cells from draining lymph nodes gain an accumulating importance in mounting anti-tumor immune response during tumorigenesis. However, in many cases, cancer cells form metastatic loci in lymph nodes before further metastasizing to distant organs. To what extent the local and systematic CD8+ T cell responses were influenced by LN metastasis remains obscure. To this end, we set up a murine LN metastasis model combined with a B16F10-GP melanoma cell line expressing the surrogate neoantigen derived from lymphocytic choriomeningitis virus (LCMV), glycoprotein (GP), and P14 transgenic mice harboring T cell receptors (TCRs) specific to GP-derived peptide GP33-41 presented by the class I major histocompatibility complex (MHC) molecule H-2Db. This protocol enables the study of antigen-specific CD8+ T cell responses during LN metastasis. In this protocol, C57BL/6J mice were subcutaneously implanted with B16F10-GP cells, followed by adoptive transfer with naive P14 cells. When the subcutaneous tumor grew to approximately 5 mm in diameter, the primary tumor was excised, and B16F10-GP cells were directly injected into the tumor draining lymph node (TdLN). Then, the dynamics of CD8+ T cells were monitored during the process of LN metastasis. Collectively, this model has provided an approach to precisely investigate the antigen-specific CD8+ T cell immune responses during LN metastasis.

Nasal Spray of Neutralizing Monoclonal Antibody 35B5 Confers Potential Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern: A Small-Scale Clinical Trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), especially the Delta and Omicron variants, have been reported to show significant resistance to approved neutralizing monoclonal antibodies (mAbs) and vaccines. We previously identified a mAb named 35B5 that harbors broad neutralization to SARS-CoV-2 VOCs. Herein, we explored the protection efficacy of a 35B5-based nasal spray against SARS-CoV-2 VOCs in a small-scale clinical trial. METHODS: We enrolled 30 healthy volunteers who were nasally administered the modified 35B5 formulation. At 12, 24, 48, and 72 hours after nasal spray, the neutralization efficacy of nasal mucosal samples was assayed with pseudoviruses coated with SARS-CoV-2 spike protein of the wild-type strain or the Alpha, Beta, Delta, or Omicron variants. RESULTS: The nasal mucosal samples collected within 24 hours after nasal spray effectively neutralized SARS-CoV-2 VOCs (including Delta and Omicron). Meanwhile, the protection efficacy was 60% effective and 20% effective at 48 and 72 hours after nasal spray, respectively. CONCLUSIONS: A single nasal spray of 35B5 formation conveys 24-hour effective protection against SARS-CoV-2 VOCs, including the Alpha, Beta, Delta, or Omicron variants. Thus, 35B5 nasal spray might be potential in strengthening SARS-CoV-2 prevention, especially in high-risk populations. CLINICAL TRIALS REGISTRATION: 2022-005-02-KY.

The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes.

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8+ T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8+ T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8+ T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8+ cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (TTSM) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-TTSM cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-TTSM cells could be harnessed to potentiate anti-tumor immunotherapy.

EZH2 restricts Tcf7 DNA methylation and promotes TFH differentiation during acute viral infection.

Follicular helper T (TFH) cells provide specialized help for B cells to ensure optimal humoral immunity. The histone methyltransferase EZH2, as a chromatin repressor, secures the TFH differentiation by promoting TFH lineage associated gene expression during acute viral infection, including Tcf7 and Bcl6. By using conditional deletion murine system, we observed that EZH2 ablation in CD4+ T cells was accompanied by aberrant accumulation of DNA methyltransferases (DNMTs) DNMT1 and DNMT3B in TFH cells. And the loss of EZH2 promoted aggravation of DNA methylation status at Tcf7 locus. Therefore, our findings suggested that EZH2 plays an important role in maintenance of hypomethylation at Tcf7 locus thus affecting TFH differentiation during acute viral infection.

CD4+ T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy.

BACKGROUND: Antitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8+ T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from tumor-derived CD8+ T-cell epitopes can drive the functional exhaustion of tumor-specific CD8+ T cells. Tumor-specific type-I helper CD4+ T (TH1) cells play an important role in the population maintenance and cytotoxic function of exhausted tumor-specific CD8+ T cells in the tumor microenvironment. Nonetheless, whether the vaccination strategy targeting MHC-II-restricted CD4+ T-cell epitopes to induce tumor-specific TH1 responses can confer effective antitumor immunity to restrain tumor growth is not well studied. Here, we developed a heterologous prime-boost vaccination strategy to effectively induce tumor-specific TH1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1/PD-L1 immunotherapy. METHODS: Listeria monocytogenes vector and influenza A virus (PR8 strain) vector stably expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein-specific I-Ab-restricted CD4+ T cell epitope (GP61-80) or ovalbumin-specific CD4+ T cell epitope (OVA323-339) were constructed and evaluated their efficacy against mouse models of melanoma and colorectal adenocarcinoma expressing lymphocytic choriomeningitis virus glycoprotein and ovalbumin. The impact of CD4+ T cell epitope-based heterologous prime-boost vaccination was detected by flow-cytometer, single-cell RNA sequencing and single-cell TCR sequencing. RESULTS: CD4+ T cell epitope-based heterologous prime-boost vaccination efficiently suppressed both mouse melanoma and colorectal adenocarcinoma. This vaccination primarily induced tumor-specific TH1 response, which in turn enhanced the expansion, effector function and clonal breadth of tumor-specific CD8+ T cells. Furthermore, this vaccination strategy synergized PD-L1 blockade mediated tumor suppression. Notably, prime-boost vaccination extended the duration of PD-L1 blockade induced antitumor effects by preventing the re-exhaustion of tumor-specific CD8+ T cells. CONCLUSION: CD4+ T cell epitope-based heterologous prime-boost vaccination elicited potent both tumor-specific TH1 and CTL response, leading to the efficient tumor control. This strategy can also potentiate PD-1/PD-L1 immune checkpoint blockade (ICB) against cancer.

The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.

Antigen-specific memory CD4+ T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4+ T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4+ T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4+ T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3ß kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4+ T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2-AKT-GSK3ß axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.

Low-Dose Albendazole Inhibits Epithelial-Mesenchymal Transition of Melanoma Cells by Enhancing Phosphorylated GSK-3ß/Tyr216 Accumulation.

Albendazole (ABZ) is an effective broad-spectrum anthelmintic agent that has been widely used for humans and animals. Previous studies have reported that ABZ exhibits antitumor effects against melanoma and other different cancer types; however, it is unknown whether ABZ exerts the inhibitory effect against melanoma metastasis. In this study, we aimed to investigate the inhibitory effect of ABZ on melanoma cells. Through in vitro studies, we discovered that low-dose ABZ treatment significantly inhibited the migration and invasion, but not the proliferation, of A375 and B16-F10 cells in a dose-dependent manner. Further analysis revealed that ABZ treatment reduced the expression level of snail family transcriptional repressor 1 (Snail) in the cytoplasm and nucleus by decreasing the levels of phosphorylated AKT (pAKT) Ser473/GSK-3ß (pGSK-3ß) Ser9 and increasing pGSK-3ß/Tyr216, resulting in a significant upregulation of E-cadherin and downregulation of N-cadherin and ultimately reversing the epithelial-mesenchymal transition (EMT) process of melanoma cells. In contrast, the continuous activation of AKT via transfected plasmids elevated the protein levels of pAKT Ser473/pGSK-3ß Ser9 and Snail and antagonized the inhibitory action of ABZ. We also confirmed that ABZ treatment effectively inhibited the lung metastasis of melanoma in nude mice in vivo. Subsequent immunohistochemical analysis verified the decreased pAKT Ser473/pGSK-3ß Ser9 and increased pGSK-3ß/Tyr216 levels in ABZ-treated subcutaneous tumors. Therefore, our findings demonstrate that ABZ treatment can suppress the EMT progress of melanoma by increasing the pGSK-3ß/Tyr216-mediated degradation of Snail, which may be used as a potential treatment strategy for metastatic melanoma.

Traceability of the geographical origin of Siraitia grosvenorii based on multielement contents coupled with chemometric techniques.

Siraitia grosvenorii (LHG) is widely used as a medicinal and edible material around the world. The objective of this study was to develop an effective method for the authentication of the geographical origin of LHG in its main producing area Guangxi, China, which is identified as Chinese Protected Designation of Origin product, against other producing regions in China. The content of 14 elements (K, Na, Ca, P, Mg, Al, B, Ba, Cu, Fe, Mn, Ni, Zn, and Sr) of 114 LHG samples was determined by inductively coupled plasma optical emission spectrometry. Multivariate analysis was then performed to classify the geographical origin of LHG samples. The contents of multielement display an obvious trend of clustering according to the geographical origin of LHG samples based on radar plot and principal component analysis. Finally, three supervised statistical techniques, including linear discriminant analysis (LDA), k-nearest neighbours (k-NN), and support vector machine (SVM), were applied to develop classification models. Finally, 40 unknown LHG samples were used to evaluate the predictive ability of model and discrimination rate of 100%, 97.5% and 100% were obtained for LDA, k-NN, and SVM, respectively. This study indicated that it is feasible to attribute unknown LHG samples to its geographical origin based on its multielement content coupled with chemometric techniques.

Facile Synthesis of P-Doped Carbon Nanosheets as Janus Electrodes of Advanced Potassium-Ion Hybrid Capacitor.

Potassium-ion hybrid capacitors (PIHCs) shrewdly integrate the merits of the high energy density of battery-type anode and the high power density of capacitor-type cathode, promising prospects for potential application in a diversity of fields. Here, we report the synthesis of P-doped porous carbon nanosheets (P-PCNs) with favorable features as electrochemical storage materials, including ultrahigh specific surface area and rich activity sites. The P-PCN as Janus electrodes show highly attractive electrochemical properties of high capacity and remarkable stability for fast K+ storage and manifest high capacitance for PF6- adsorption. The P-PCNs are applied as both anode and cathode materials to set up dual-carbon PIHCs, which show the capability to deliver a high energy/power density (165.2 Wh kg-1 and 5934.4 W kg-1) as well as remarkable long-life capability.

Hierarchical Multicavity Nitrogen-Doped Carbon Nanospheres as Efficient Polyselenide Reservoir for Fast and Long-Life Sodium-Selenium Batteries.

Sodium-selenium (Na-Se) battery has been emerging as one of the most prospective energy storage systems owing to their high volumetric energy density and cost effectiveness. Nevertheless, the shuttle effect of sodium polyselenide (NaPSe) and sluggish electrochemical reaction kinetics present the main bottlenecks for its practical implementation. Herein, a new Se host of 3D nitrogen-doped hierarchical multicavity carbon nanospheres (3D NHMCs) is designed and synthesized via a facile self-sacrifice templating strategy. The 3D NHMCs are verified to hold a favorable structure of a hollow macropore core and numerous micro/mesopores hollow shell for hosting Se, which can not only maximize Se utilization and alleviate the volumetric expansion but also promote the electrical/ionic conductivity and electrolyte infiltration. Moreover, the abundant self-functionalized surfaces as an efficient NaPSe scavenger via robust physical-chemical dual blocking effects demonstrate high-efficiency in situ anchoring-diffusion-conversion of NaPSe, rendering rapid reaction kinetics and remarkable suppressive shuttle effect, as evidenced by systematic experimental analysis and density functional theory calculations. As a result, the high-Se-loading 3D NHMCs/Se cathode exhibits an ultrahigh volumetric capacity (863 mAh cm-3 ) and rate capability (377 mAh g-1 at 20 C) and unexceptionable stability over 2000 cycles at 2 C.

Hepatic NPC1L1 overexpression attenuates alcoholic autophagy in mice.

Alcohol consumption causes liver steatosis in humans. Metabolic disorders of lipids are one of the factors that cause liver steatosis in hepatocytes. Hepatic Niemann­Pick C1­like 1 (NPC1L1) regulates lipid homeostasis in mammals. The relationship between NPC1L1 and autophagy in those with a history of alcohol abuse is unclear. The present study aimed to investigate the function of NPC1L1 in the activation of hepatic autophagy in a mouse model with a human (h)NPC1L1 transgene under alcohol feeding conditions. The mice expressing hNPC1L1 (Ad­L1) or controls (Ad­null) were created by retro­orbital adenovirus injection. The Ad­L1 and Ad­null mice were fed with alcohol or a non­alcoholic diet to mimic chronic alcohol consumption in humans. Hepatic autophagy was demonstrated in isolated primary hepatocytes by monitoring autophagic vacuoles under fluorescence microscopy, and by western blotting for autophagic makers. Isolated hepatocytes from the livers of Ad­L1 mice were treated with different doses of ezetimibe to study the restoration of autophagy. Chronic alcohol feeding caused liver injury and steatosis, shown by significantly higher levels of plasma alanine transaminase and aspartate transaminase activity, and by hematoxylin and eosin staining in Ad­L1 and Ad­null mice. Compared to Ad­null control mice, the microtubule­associated proteins 1A/1B light chain 3 (LC3) particles in the isolated hepatocytes of Ad­L1 mice were decreased, both under alcohol and non­alcoholic feeding. The ratio of LC3II/LC3I was significantly decreased, and the level of p62/sequestosome­1 protein was significantly increased in Ad­L1 mice compared with Ad­null mice after alcohol feeding. Levels of LC3II protein were statistically increased in hepatocytes isolated from Ad­L1 mice with ezetimibe treatment. The increase in LC3II expression was dose dependent. Within the tested range, it reached its highest level at 40 µM. The livers of Ad­L1 mice represent a more human­like state for the study of hepatic autophagy. Hepatic expression of human NPC1L1 resulted in an inhibition of autophagy; it may contribute to alcoholic fatty liver disease in humans.

Electronic Health Record Driven Prediction for Gestational Diabetes Mellitus in Early Pregnancy.

Gestational diabetes mellitus (GDM) is conventionally confirmed with oral glucose tolerance test (OGTT) in 24 to 28 weeks of gestation, but it is still uncertain whether it can be predicted with secondary use of electronic health records (EHRs) in early pregnancy. To this purpose, the cost-sensitive hybrid model (CSHM) and five conventional machine learning methods are used to construct the predictive models, capturing the future risks of GDM in the temporally aggregated EHRs. The experimental data sources from a nested case-control study cohort, containing 33,935 gestational women in West China Second Hospital. After data cleaning, 4,378 cases and 50 attributes are stored and collected for the data set. Through selecting the most feasible method, the cost parameter of CSHM is adapted to deal with imbalance of the dataset. In the experiment, 3940 samples are used for training and the rest 438 samples for testing. Although the accuracy of positive samples is barely acceptable (62.16%), the results suggest that the vast majority (98.4%) of those predicted positive instances are real positives. To our knowledge, this is the first study to apply machine learning models with EHRs to predict GDM, which will facilitate personalized medicine in maternal health management in the future.

The preclinical analysis of TW-37 as a potential anti-colorectal cancer cell agent.

TW-37 is a novel, potent and non-peptide Bcl-2 small-molecule inhibitor. Its activity in colorectal cancer (CRC) cells is studied. In both HCT-116 cells and primary human colon cancer cells, treatment with TW-37 at only nM concentration efficiently inhibited cell survival and proliferation. TW-37 also induced caspase-3/9 and apoptosis activation in CRC cells. Feedback autophagy activation was observed in TW-37-treated CRC cells. Reversely pharmacological autophagy inhibition or Beclin-1 knockdown by targeted-shRNA potentiated TW-37-induced apoptosis and killing of CRC cells. In vivo, intravenous injection of TW-37 inhibited HCT-116 tumor growth in mice. TW-37's anti-tumor activity was further potentiated against Beclin-1-silenced HCT-116 tumors. Together, targeting Bcl-2 family protein by TW-37 efficiently inhibits CRC cell growth in vitro and in vivo. Inhibition of feedback autophagy activation could further sensitize TW-37.

ROCK is involved in vimentin phosphorylation and rearrangement induced by dengue virus.

Our previous study showed that dengue virus 2 (DENV2) infection induces rearrangement of vimentin into dense structures at the perinuclear area. However, the underlying mechanism of this phenomenon is poorly characterized. In the present work, we found that vimentin and Ser71 phosphorylated vimentin display similar distributions in DENV2-infected cells. DENV2 infection also induced ROCK activation and phosphorylation of vimentin at Ser71 as the DENV2 infection progressed. Furthermore, Ser71 phosphorylation and vimentin rearrangement induced by DENV2 infection were blocked by the ROCK inhibitor Y-27632. In addition, DENV2 led to endoplasmic reticulum (ER) redistribution in the perinuclear region of the host cells, which was partially blocked by pretreatment with Y-27632. Together, these data support indicate that ROCK may have a role in governing regulating vimentin and ER rearrangement during DENV2 infection. We hypothesize that DENV2 infection, via ROCK activation, induces both vimentin rearrangement and ER redistribution around the perinuclear region, which may play a structural role in anchoring DENV2 to replication sites.