Frequency-Hopping Wave Engineering with Metasurfaces

Wave phenomena can be artificially engineered by scattering from metasurfaces, which aids in the design of radio-frequency and optical devices for wireless communication, sensing, imaging, wireless power transfer and bio/medical applications. Scattering responses vary with changing frequency; conversely, they remain unchanged at a constant frequency, which has been a long-standing limitation in the design of devices leveraging wave scattering phenomena. Here, we present metasurfaces that can scatter incident waves according to two variables - the frequency and pulse width - in multiple bands. Significantly, these scattering profiles are characterized by how the frequencies are used in different time windows due to transient circuits. In particular, with coupled transient circuits, we demonstrate variable scattering profiles in response to unique frequency sequences, which can markedly increase the available frequency channels in accordance with a factorial function. Our proposed concept, which is analogous to frequency hopping in wireless communication, advances wave engineering in electromagnetics and related fields.Comment: 62 pages, 25 figure

Inhibitory mechanisms of LAG-3–dependent T cell suppression

T cell activation is tightly regulated by both stimulatory and inhibitory co-receptors and has been a focus in the development of interventions for managing cancer or autoimmune diseases. Targeting the inhibitory co-receptors programmed cell death 1 (PD-1) and cytotoxic T lymphocyte–associated protein 4 (CTLA-4) has successfully eradicated tumors but induced immune-related adverse events in humans and mice. The beneficial and adverse effects of targeting these co-receptors highlight their importance in cancer immunity and also autoimmunity. Although the therapeutic potencies of other inhibitory co-receptors are under extensive investigation, their inhibitory mechanisms and their functional differences are not well understood. Here we analyzed the inhibitory mechanisms of lymphocyte activation gene-3 (LAG-3), another inhibitory co-receptor, by using an in vitro T cell activation system and a high-affinity anti-LAG-3 antibody that strongly interferes with the binding of LAG-3 to its ligand. We found that the expression level of LAG-3 strongly correlates with the inhibitory function of LAG-3, suggesting that LAG-3 functions as a rheostat rather than as a breaker of T cell activation. By evaluating the inhibitory capacities of various LAG-3 variants relative to their expression levels, we found that LAG-3 transduces two independent inhibitory signals through an FXXL motif in the membrane-proximal region and the C-terminal EX repeat. These motifs have not been reported previously for inhibitory co-receptors, suggesting that LAG-3 inhibits T cell activation through a nonredundant inhibitory mechanisms along with the other inhibitory co-receptors. Our findings provide a rationale for combinatorial targeting of LAG-3 and the other inhibitory co-receptors to improve cancer immunotherapy

Bacterial inducible expression of plant cell wall-binding protein YesO through conflict between Glycine max and saprophytic Bacillus subtilis

大豆と納豆菌のせめぎ合いの仕組みを解明 --生きた大豆は納豆菌を嫌い、納豆菌は死んだ大豆が好き--. 京都大学プレスリリース. 2020-11-02.Saprophytic bacteria and plants compete for limited nutrient sources. Bacillus subtilis grows well on steamed soybeans Glycine max to produce the fermented food, natto. Here we focus on bacterial responses in conflict between B. subtilis and G. max. B. subtilis cells maintained high growth rates specifically on non-germinating, dead soybean seeds. On the other hand, viable soybean seeds with germinating capability attenuated the initial growth of B. subtilis. Thus, B. subtilis cells may trigger saprophytic growth in response to the physiological status of G. max. Scanning electron microscope observation indicated that B. subtilis cells on steamed soybeans undergo morphological changes to form apertures, demonstrating cell remodeling during saprophytic growth. Further, transcriptomic analysis of B. subtilis revealed upregulation of the gene cluster, yesOPQR, in colonies growing on steamed soybeans. Recombinant YesO protein, a putative, solute-binding protein for the ATP-binding cassette transporter system, exhibited an affinity for pectin-derived oligosaccharide from plant cell wall. The crystal structure of YesO, in complex with the pectin oligosaccharide, was determined at 1.58 Å resolution. This study expands our knowledge of defensive and offensive strategies in interspecies competition, which may be promising targets for crop protection and fermented food production

Glucocorticoids strengthen PD-1 effects

The inhibitory co-receptor programmed cell death 1 (PD-1, Pdcd1) plays critical roles in the regulation of autoimmunity, anti-cancer immunity, and immunity against infections. Immunotherapies targeting PD-1 have revolutionized cancer management and instigated various trials of improved cancer immunotherapies. Moreover, extensive trials are underway to potentiate PD-1 function in order to suppress harmful immune responses. Here, we found that both natural and synthetic glucocorticoids (GCs) up-regulate PD-1 on T cells without altering the expression levels of other co-receptors and cell-surface molecules. The GC-induced up-regulation of PD-1 depended on the transactivation of PD-1 transcription mediated through the glucocorticoid receptor (GR). We further found that a GC response element (GRE) 2525 bp upstream from the transcription start site of Pdcd1 is responsible for GC-mediated transactivation. We also observed that in vivo administration of GCs significantly up-regulates PD-1 expression on tumor-infiltrating T cells. By analyzing T cells differing in PD-1 expression, we directly demonstrated that the amount of PD-1 on the cell surface correlates with its inhibitory effect. Accordingly, GCs potentiated the capacity of PD-1 to inhibit T cell activation, suggesting that this PD-1-mediated inhibition contributes, at least in part, to the anti-inflammatory and immunosuppressive effects of GCs. In light of the critical roles of PD-1 in the regulation of autoimmunity regulation, we expect that the potentiation of PD-1 activity may offer a promising therapeutic strategy for managing inflammatory and autoimmune diseases. Our current findings provide a rationale for strategies seeking to enhance the inhibitory effect of PD-1 by increasing its expression level

PD-1 Primarily Inhibits TCR Signal

Cancer-immunotherapy targeting programmed cell death 1 (PD-1) activates tumor-specific T cells and provides clinical benefits in various cancers. However, the molecular basis of PD-1 function is still enigmatic. Especially, it is unclear which signaling pathway PD-1 primarily targets. Besides, the capacity of PD-1 to inhibit the T cell receptor (TCR)-dependent activation of T cells in the presence of co-stimulation is also controversial. Here we used co-culture systems of T cells and antigen-presenting cells with targeted deletion and overexpression of co-receptors and ligands and examined the inhibitory potency of PD-1 against T cell activation upon TCR stimulation with CD28 and ICOS co-stimulation. As an unambiguous criterion of T cell activation, we used the acquisition of cytokine production capacity, which represents one of the most important functions of T cells. PD-1 inhibited functional T cell activation upon TCR stimulation in the absence as well as in the presence of CD28 co-stimulation, indicating that PD-1 can directly inhibit TCR signal. Notably, CD28 co-stimulation rather attenuated the efficiency of PD-1 in inhibiting TCR-dependent functional T cell activation. In addition, PD-1 inhibited TCR-dependent functional T cell activation with ICOS co-stimulation as efficiently as that with CD28 co-stimulation. Furthermore, we found that the maintenance of antigen-induced follicular helper T (TFH) cells that required ICOS co-stimulation was persistently restrained by PD-1 in vivo. These findings indicate that PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Thus, PD-1 functions as the rheostat of T cell activation rather than an inhibitor of a specific stimulatory co-receptor

PD-1は自己反応性CD８陽性T細胞の活性化経路を遮断して細胞傷害機能の獲得を阻止する

Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8+ T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single-cell mRNA expression profiling of autoreactive CD8+ T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8+ T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8+ T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8+ T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities

Detection of Salivary miRNAs That Predict Chronic Periodontitis Progression: A Cohort Study

The aim of this two-year cohort study was to investigate salivary microRNAs (miRNAs) that predict periodontitis progression. A total of 120 patients who underwent supportive periodontal therapy were recruited. Unstimulated whole saliva was collected at baseline. Two years later, 44 patients were followed up (median age, 67.1 years) and divided into two groups: progression group (n = 22), with one or more sites with clinical attachment level (CAL) progression (>3 mm compared with baseline) or tooth extraction due to periodontitis progression; and the control group (n = 22), which did not exhibit CAL progression. In the microarray analysis of salivary miRNAs, hsa-miR-5571-5p, hsa-miR-17-3p, hsa-let-7f-5p, hsa-miR-4724-3p, hsa-miR-99a-5p, hsa-miR-200a-3p, hsa-miR-28-5p, hsa-miR-320d, and hsa-miR-31-5p showed fold change values = 2.0 in the progression group compared with the control group (p 0.7, indicating fair discrimination power. The expressions of salivary hsa-miR-5571-5p, hsa-let-7f-5p, hsa-miR-99a-5p, hsa-miR-28-5p, and hsa-miR-320d were associated with periodontitis progression in patients with chronic periodontitis. These salivary miRNAs may be new biomarkers for progression of periodontitis, and monitoring them may contribute to new diagnostics and precision medicine for periodontitis

Retrospective Cohort Study Showing Clinical Equivalence of Microendoscopic Laminotomy to Open Fenestration for Patients with Lumbar Spinal Stenosis

Objective Despite the popularity of microendoscopic disectomy, there is currently insufficient studies about microendoscopic laminotomy (MEL) for lumbar spinal stenosis. The purpose of this study was to compare the clinical and radiographic outcomes of MEL and fenestration (laminotomy in open procedure) for lumbar spinal stenosis. Methods This study included 30 patients in the MEL group and 46 patients in the open fenestration group between 2012 and 2016 (follow-up period ≥1 year). The Japanese Orthopedic Association Back Pain Evaluation Questionnaire(JOABPEQ), a visual analog scale(VAS), surgical outcomes, blood test outcomes, and radiographic parameters were studied. Results Mean age was 67 years old in the MEL group and 70 years old in the open fenestration group (p=0.1). There were no significant differences in score change of either domain of JOABPEQ between MEL and fenestration. The 95% confidence intervals of the between-group differences in score change were within clinical important difference (±20 point) in all the domains of JOABPEQ. The MEL group had significantly shorter hospital stays (9 days vs 13 days; p<0.001), smaller increase in C-reactive protein (1.7 mg/dL vs 2.9 mg/dL; p=0.009), and longer operating time (122 min vs 39 min; p<0.001) than the fenestration group. There was no significant difference in hemoglobin level, total protein, albumin, creatine kinase between the groups. The MEL group had one case of dural tear and the fenestration group had two cases(p=1.0). There was no significant differences in complication rate between the groups. There were no significant between-group differences in change of disc height or ROM. Conclusion In the treatment of lumbar spinal stenosis, the clinical effectiveness and safety of MEL was equivalent to that of fenestration, with less invasiveness

Ganglion cyst arising from the infrapatellar fat pad in a child

A ganglion cyst is a cystic lesion containing myxoid matrix and lined by a pseudomembrane. A ganglion cyst arising from the infrapatellar fat pad is very rare, with only a few reports appearing in the literature, and the present case is the first report of this lesion in a child. A 10-year-old boy presented with right knee pain that showed no improvement despite resting from sports activity for 1 month. Magnetic resonance imaging revealed a multilobular mass between the infrapatellar fat pad and anterior cruciate ligament. Arthroscopic excision of the mass was performed. The mass was noted to arise from the infrapatellar fat pad and was filled with myxoid matrix. The histological diagnosis was a ganglion cyst. In active pediatric patients with pain or limited range of motion in the knee, physicians should consider the possibility of a ganglion cyst from the infrapatellar fat pad, despite its rarity