Phonon-Polaritons in Lead Halide Perovskite Film Hybridized with THz Metamaterials.

In this work, we demonstrated a phonon-polariton in the terahertz (THz) frequency range, generated in a crystallized lead halide perovskite film coated on metamaterials. When the metamaterial resonance was in tune with the phonon resonance of the perovskite film, Rabi splitting occurred due to the strong coupling between the resonances. The Rabi splitting energy was about 1.1 meV, which is larger than the metamaterial and phonon resonance line widths; the interaction potential estimation confirmed that the strong coupling regime was reached successfully. We were able to tune the polaritonic branches by varying the metamaterial resonance, thereby obtaining the dispersion curve with a clear anticrossing behavior. Additionally, we performed in situ THz spectroscopy as we annealed the perovskite film and studied the Rabi splitting as a function of the films' crystallization coverage. The Rabi splitting versus crystallization volume fraction exhibited a unique power-law scaling, depending on the crystal growth dimensions.

Genotypic Heterogeneity of Orientia tsutsugamushi in Scrub Typhus Patients and Thrombocytopenia Syndrome Co-infection, Myanmar.

Serologic and molecular surveillance of serum collected from 152 suspected scrub typhus patients in Myanmar revealed Orientia tsutsugamushi of genotypic heterogeneity. In addition, potential co-infection with severe fever with thrombocytopenia syndrome virus was observed in 5 (3.3%) patients. Both scrub typhus and severe fever with thrombocytopenia syndrome are endemic in Myanmar.

Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90ß as a Novel Mechanism of Rifampin-induced MDR1 Expression.

The P-glycoprotein (P-gp) encoded by the MDR1 gene is a drug-exporting transporter located in the cellular membrane. P-gp induction is regarded as one of the main mechanisms underlying drug-induced resistance. Although there is great interest in the regulation of P-gp expression, little is known about its underlying regulatory mechanisms. In this study, we demonstrate that casein kinase 2 (CK2)-mediated phosphorylation of heat shock protein 90ß (Hsp90ß) and subsequent stabilization of PXR is a key mechanism in the regulation of MDR1 expression. Furthermore, we show that CK2 is directly activated by rifampin. Upon exposure to rifampin, CK2 catalyzes the phosphorylation of Hsp90ß at the Ser-225/254 residues. Phosphorylated Hsp90ß then interacts with PXR, causing a subsequent increase in its stability, leading to the induction of P-gp expression. In addition, inhibition of CK2 and Hsp90ß enhances the down-regulation of PXR and P-gp expression. The results of this study may facilitate the development of new strategies to prevent multidrug resistance and provide a plausible mechanism for acquired drug resistance by CK2-mediated regulation of P-gp expression.

Electrically tunable liquid crystal laser using a nanoimprinted indium-tin-oxide electrode as a distributed feedback resonator.

We demonstrated electrical tunability of a liquid crystal (LC) laser using a nanoimprinted indium-tin-oxide (ITO) film as a distributed feedback (DFB) resonator, a transparent electrode, and an alignment layer for LCs. From the field-induced reorientation of LCs and changes in effective refractive indices of guided laser modes, lasing emission is tuned by 6 nm at low applied voltage of 8.0 V. This is because the LC laser with the nanoimprinted ITO electrode has no additional insulating layers for lasing performance. The present system is based on the functional electrode and its active control provides various applications and advances in laser technology.

Generation of protective immunity against Orientia tsutsugamushi infection by immunization with a zinc oxide nanoparticle combined with ScaA antigen.

BACKGROUND: Zinc oxide nanoparticle (ZNP) has been applied in various biomedical fields. Here, we investigated the usage of ZNP as an antigen carrier for vaccine development by combining a high affinity peptide to ZNP. RESULTS: A novel zinc oxide-binding peptide (ZBP), FPYPGGDA, with high affinity to ZNP (K a  = 2.26 × 106 M-1) was isolated from a random peptide library and fused with a bacterial antigen, ScaA of Orientia tsutsugamushi, the causative agent of scrub typhus. The ZNP/ZBP-ScaA complex was efficiently phagocytosed by a dendritic cell line, DC2.4, in vitro and significantly enhanced anti-ScaA antibody responses in vivo compared to control groups. In addition, immunization with the ZNP/ZBP-ScaA complex promoted the generation of IFN-γ-secreting T cells in an antigen-dependent manner. Finally, we observed that ZNP/ZBP-ScaA immunization provided protective immunity against lethal challenge of O. tsutsugamushi, indicating that ZNP can be used as a potent adjuvant when complexed with ZBP-conjugated antigen. CONCLUSIONS: ZNPs possess good adjuvant potential as a vaccine carrier when combined with an antigen having a high affinity to ZNP. When complexed with ZBP-ScaA antigen, ZNPs could induce strong antibody responses as well as protective immunity against lethal challenges of O. tsutsugamushi. Therefore, application of ZNPs combined with a specific soluble antigen could be a promising strategy as a novel vaccine carrier system.

Universal Efficiency Improvement in Organic Solar Cells Based on a Poly(3-hexylthiophene) Donor and an Indene-C60 Bisadduct Acceptor with Additional Donor Nanowires.

With poly(3-hexylthiophene) (P3HT) nanowire (NW) inclusion in active layers (ALs), organic solar cells (OSCs) based on P3HT donor and indene-C60 bisadduct (ICBA) acceptor showed power conversion efficiency (PCE) improvements for both bulk heterojunction (BHJ)- and bilayer (BL)-structure AL devices. The PCE increase was approximately 14 % for both types of P3HT:ICBA OSCs. However, improvements in short-circuit current density (Jsc ) were about 4.4 and 6.4 % for BHJ- and BL-type AL devices, respectively. A systematic study showed that the addition of P3HT NWs did not result in enhanced internal quantum efficiencies for either type of device. However, the difference in light-harvesting efficiency was important in accounting for Jsc variations. Interestingly, there was no correlation between Jsc and PCE variations, whereas the open-circuit voltage (Voc ) and fill factor (FF) showed correlations with the PCE. The variation in FF is discussed in terms of Voc and equivalent-circuit parameters based on a nonideal diode model.

Active escape of Orientia tsutsugamushi from cellular autophagy.

Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular pathogen. After entry into host cells, the bacterium rapidly escapes from the endosomal pathway and replicates in the cytosol of eukaryotic host cells. Here we show that O. tsutsugamushi infection efficiently promotes cellular autophagy, a cell-autonomous defense mechanism of innate immunity. However, most of the internalized bacteria barely colocalized with the induced autophagosomes, even when stimulated with rapamycin, a chemical inducer of autophagy. Treatment of infected cells with tetracycline suppressed bacterial evasion from autophagy and facilitated O. tsutsugamushi targeting to autophagosomes, suggesting that the intracellular pathogen may be equipped with a bacterial factor or factors that block autophagic recognition. Finally, we also found that chemical modulators of cellular autophagy or genetic knockout of the atg3 gene does not significantly affect the intracellular growth of O. tsutsugamushi in vitro. These results suggest that O. tsutsugamushi has evolved to block autophagic microbicidal defense by evading autophagic recognition even though it activates the autophagy pathway during the early phase of infection.

Hybridized Local and Charge-Transfer Excited-State Emitter for a Blue Organic Solid-State Laser.

The use of triplet excitons harvesting and short exciton lifetime organic emitters is important to improve the exciton utilization in organic semiconductor laser diodes. In this study, a hybridized local and charge-transfer (HLCT)-type molecule, 11-(3-(10-(4-(1-phenyl-1H-phenanthro[9,10-d]imidazol-2-yl)phenyl)anthracen-9-yl)phenyl)-11H-benzofuro[3,2-b]carbazole (PhAnMBf), is used as an emitter for blue-emitting organic solid-state lasers (OSSLs). The short exciton lifetime and high photoluminescence quantum yield of the PhAnMBf emitter allowed the fabrication of an organic laser with an emission wavelength of 453 nm, a small full width at half-maximum of 1.2 nm, and a threshold of 105 nJ/pulse, corresponding to 44 µJ/cm2, on the distributed feedback substrate. The anthracene-based PhAnMBf material showed the potential of the HLCT emitter as an OSSL.

An Alternative Splicing Variant of the Mixed-Lineage Leukemia 5 Protein Is a Cellular Adhesion Receptor for ScaA of Orientia tsutsugamushi.

Scrub typhus is a mite-borne disease caused by the obligately intracellular bacterium Orientia tsutsugamushi. We previously demonstrated that ScaA, an autotransporter membrane protein of O. tsutsugamushi, is commonly shared in various genotypes and involved in adherence to host cells. Here, we identified a mixed-lineage leukemia 5 (MLL5) mammalian trithorax group protein as a host receptor that interacts with ScaA. MLL5, identified by yeast two-hybrid screening, is an alternative splicing variant of MLL5 (vMLL5) which contains 13 exons with additional intron sequences encoding a tentative transmembrane domain. Indeed, vMLL5 is expressed on the plasma membrane as well as in intracellular compartments in eukaryotic cells and colocalized with adherent O. tsutsugamushi. In addition, ScaA-expressing Escherichia coli showed significantly increased adherence to vMLL5-overexpressing cells compared with vector control cells. We mapped the C-terminal region of the passenger domain of ScaA as a ligand for vMLL5 and determined that the Su(var)3-9, Enhancer of zeste, Trithorax (SET) domain of MLL5 is an essential and sufficient motif for ScaA binding. We observed significant and specific inhibition of bacterial adhesion to host cells in competitive inhibition assays using the C-terminal fragment of ScaA or the SET domain of vMLL5. Moreover, immunization with the C-terminal fragment of ScaA provided neutralizing activity and protective immunity against lethal challenge with O. tsutsugamushi as efficiently as vaccination with the whole passenger domain of ScaA. These results indicate that vMLL5 is a novel cellular receptor for ScaA-mediated adhesion of O. tsutsugamushi and facilitates bacterial adhesion to host cells, thereby enhancing bacterial infection. IMPORTANCE O. tsutsugamushi is a mite-borne pathogen that causes scrub typhus. As an obligately intracellular pathogen, its adhesion to and invasion of host cells are critical steps for bacterial growth. However, the molecular basis of the bacterial ligand and host receptor interaction is poorly defined. Here, we identified a splicing variant of MLL5 (vMLL5) as a cellular adhesion receptor of ScaA, an outer membrane autotransporter protein of O. tsutsugamushi. We mapped the interacting domains in the bacterial ligand and host receptor and confirmed their functional interaction. In addition, immunization with the C-terminal region of ScaA, which involves an interaction with the SET domain of vMLL5, not only induces enhanced neutralizing antibodies but also provides protective immunity against lethal challenge with O. tsutsugamushi.

Corrigendum: Acute surge of atypical memory and plasma B-cell subsets driven by an extrafollicular response in severe COVID-19.

[This corrects the article DOI: 10.3389/fcimb.2022.909218.].

Corrigendum: Differential association of viral dynamics with disease severity depending on patients' age group in COVID-19.

[This corrects the article DOI: 10.3389/fmicb.2021.712260.].

A single-cell atlas of in vitro multiculture systems uncovers the in vivo lineage trajectory and cell state in the human lung.

We present an in-depth single-cell atlas of in vitro multiculture systems on human primary airway epithelium derived from normal and diseased lungs of 27 individual donors. Our large-scale single-cell profiling identified new cell states and differentiation trajectories of rare airway epithelial cell types in human distal lungs. By integrating single-cell datasets of human lung tissues, we discovered immune-primed subsets enriched in lungs and organoids derived from patients with chronic respiratory disease. To demonstrate the full potential of our platform, we further illustrate transcriptomic responses to various respiratory virus infections in vitro airway models. Our work constitutes a single-cell roadmap for the cellular and molecular characteristics of human primary lung cells in vitro and their relevance to human tissues in vivo.

Elevated IFNA1 and suppressed IL12p40 associated with persistent hyperinflammation in COVID-19 pneumonia.

Introduction: Despite of massive endeavors to characterize inflammation in COVID-19 patients, the core network of inflammatory mediators responsible for severe pneumonia stillremain remains elusive. Methods: Here, we performed quantitative and kinetic analysis of 191 inflammatory factors in 955 plasma samples from 80 normal controls (sample n = 80) and 347 confirmed COVID-19 pneumonia patients (sample n = 875), including 8 deceased patients. Results: Differential expression analysis showed that 76% of plasmaproteins (145 factors) were upregulated in severe COVID-19 patients comparedwith moderate patients, confirming overt inflammatory responses in severe COVID-19 pneumonia patients. Global correlation analysis of the plasma factorsrevealed two core inflammatory modules, core I and II, comprising mainly myeloid cell and lymphoid cell compartments, respectively, with enhanced impact in a severity-dependent manner. We observed elevated IFNA1 and suppressed IL12p40, presenting a robust inverse correlation in severe patients, which was strongly associated with persistent hyperinflammation in 8.3% of moderate pneumonia patients and 59.4% of severe patients. Discussion: Aberrant persistence of pulmonary and systemic inflammation might be associated with long COVID-19 sequelae. Our comprehensive analysis of inflammatory mediators in plasmarevealed the complexity of pneumonic inflammation in COVID-19 patients anddefined critical modules responsible for severe pneumonic progression.

Corrigendum: Elevated IFNA1 and suppressed IL12p40 associated with persistent hyperinflammation in COVID-19 pneumonia.

[This corrects the article DOI: 10.3389/fimmu.2023.1101808.].

Distinct Motifs in ATAD5 C-Terminal Domain Modulate PCNA Unloading Process.

Proliferating cell nuclear antigen (PCNA) is a DNA clamp that functions in key roles for DNA replication and repair. After the completion of DNA synthesis, PCNA should be unloaded from DNA in a timely way. The ATAD5-RFC-Like Complex (ATAD5-RLC) unloads PCNA from DNA. However, the mechanism of the PCNA-unloading process remains unclear. In this study, we determined the minimal PCNA-unloading domain (ULD) of ATAD5. We identified several motifs in the ATAD5 ULD that are essential in the PCNA-unloading process. The C-terminus of ULD is required for the stable association of RFC2-5 for active RLC formation. The N-terminus of ULD participates in the opening of the PCNA ring. ATAD5-RLC was more robustly bound to open-liable PCNA compared to the wild type. These results suggest that distinct motifs of the ATAD5 ULD participate in each step of the PCNA-unloading process.

Acute Surge of Atypical Memory and Plasma B-Cell Subsets Driven by an Extrafollicular Response in Severe COVID-19.

Background: Despite the use of vaccines and therapeutics against the coronavirus disease 2019 (COVID-19) pandemic, this severe disease has been a critical burden on public health, whereas the pathogenic mechanism remains elusive. Recently, accumulating evidence underscores the potential role of the aberrant B-cell response and humoral immunity in disease progression, especially in high-risk groups. Methods: Using single-cell RNA (scRNA) sequencing analysis, we investigated transcriptional features of B-cell population in peripheral blood from COVID-19 patients and compared them, according to clinical severity and disease course, against a public B-cell dataset. Results: We confirmed that acute B cells differentiate into plasma cells, particularly in severe patients, potentially through enhanced extrafollicular (EF) differentiation. In severe groups, the elevated plasma B-cell response displayed increased B-cell receptor (BCR) diversity, as well as higher levels of anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) spike antibodies in plasma, than those in moderate cases, suggesting more robust and heterogeneous plasma cell response in severe COVID-19 patients. Trajectory analysis identified a differentiation pathway for the EF B-cell response from active naïve to atypical memory B cells (AM2), in addition to the emergence of an aberrant plasma cell subset (PC2), which was associated with COVID-19 progression and severity. The AM2 and PC2 subsets surged in the acute phase of the severe disease and presented multiple inflammatory features, including higher cytokine expression and humoral effector function, respectively. These features differ from other B-cell subsets, suggesting a pathogenic potential for disease progression. Conclusion: The acute surge of AM2 and PC2 subsets with lower somatic hypermutation and higher inflammatory features may be driven by the EF B-cell response during the acute phase of severe COVID-19 and may represent one of the critical drivers in disease severity.

Eosinophil-mediated lung inflammation associated with elevated natural killer T cell response in COVID-19 patients.

BACKGROUND/AIMS: Coronavirus disease 2019 (COVID-19) is associated with acute respiratory syndrome. The mechanisms underlying the different degrees of pneumonia severity in patients with COVID-19 remain elusive. This study provides evidence that COVID-19 is associated with eosinophil-mediated inflammation. METHODS: We performed a retrospective case series of three patients with laboratory and radiologically confirmed COVID-19 pneumonia admitted to Chosun University Hospital. Demographic and clinical data on inflammatory cell lung infiltration and cytokine levels in patients with COVID-19 were collected. RESULTS: Cytological analysis of sputum, tracheal aspirates, and bronchoalveolar lavage fluid (BALF) samples from all three patients revealed massive infiltration of polymorphonuclear cells (PMNs), such as eosinophils and neutrophils. All sputum and BALF specimens contained high levels of eosinophil cationic proteins. The infiltration of PMNs into the lungs, together with elevated levels of natural killer T (NKT) cells in BALF and peripheral blood samples from patients with severe pneumonia in the acute phase was confirmed by flow cytometry. CONCLUSION: These results suggest that the lungs of COVID-19 patients can exhibit eosinophil-mediated inflammation, together with an elevated NKT cell response, which is associated with COVID-19 pneumonia.

An autotransporter protein from Orientia tsutsugamushi mediates adherence to nonphagocytic host cells.

Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular pathogen whose mechanism of cellular adhesion and invasion is poorly characterized. Bioinformatic analyses of two O. tsutsugamushi genomes revealed the presence of a group of genes that encode autotransporter proteins. In this study, we identified 10 autotransporter gene products and categorized them into five groups of orthologs (ScaA to ScaE) based on their sequence similarities. Sequence homology was highest between members of ScaC group, suggesting the functional conservation of bacterium-host interactions. ScaC was actively expressed on the surface of O. tsutsugamushi and induced antibody responses in scrub typhus patients. Experiments using microbeads conjugated to recombinant ScaC or a surrogate Escherichia coli expression system showed that ScaC was sufficient to mediate attachment to, but not invasion of, nonphagocytic mammalian cells. In addition, preincubation of host cells with recombinant ScaC significantly inhibited their interaction with O. tsutsugamushi. Finally, fibronectin was identified as a potential receptor for ScaC by using yeast two-hybrid screening, and this was confirmed using a glutathione S-transferase (GST) pulldown assay. Taken together, these results demonstrate that ScaC is involved in the interaction of O. tsutsugamushi with mammalian host cells and suggest that ScaC may play a critical role in bacterial pathogenesis.

Transgenic overexpression of p23 induces spontaneous hydronephrosis in mice.

p23 is a cochaperone of heat shock protein 90 and also interacts functionally with numerous steroid receptors and kinases. However, the in vivo roles of p23 remain unclear. To explore its in vivo function, we generated the transgenic (TG) mice ubiquitously overexpressing p23. The p23 TG mice spontaneously developed kidney abnormalities closely resembling human hydronephrosis. Consistently, kidney functions deteriorate significantly in the p23 TG mice compared to their wild-type (WT) littermates. Furthermore, the expression of target genes for aryl hydrocarbon receptor (AhR), such as cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1A1) and cytochrome P450, family 1, subfamily B, polypeptide 1 (Cyp1B1), were induced in the kidneys of the p23 TG mice. These results indicate that the overexpression of p23 contributes to the development of hydronephrosis through the upregulation of the AhR pathway in vivo.

Nanostructured indium-tin-oxide films fabricated by all-solution processing for functional transparent electrodes.

We investigated nanostructured indium-tin-oxide (ITO) films fabricated by all-solution processing of ITO nanoparticles and a nanoimprint lithography technique. The nanostructured ITO film with one-dimensional periodicity has low sheet resistance of ~200 Ω/sq, high optical transparency of ~80%, and specific transmission spectra due to light diffractions. By using this ITO film as a transparent electrode and an alignment layer of nematic liquid crystals (LCs), we successfully demonstrate the electro-optic performance of LC devices. This functional transparent electrode can give rise to new photonic devices with nanostructures.