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Streptococcus pneumoniae is a common human nasopharyngeal commensal colonizing 10% to 40% of healthy individuals, depending on age. Despite a low invasive disease rate, widespread carriage ensures that infection occurs often enough to make S. pneumoniae a leading bacterial cause of respiratory disease worldwide. However, the mechanisms behind transition from asymptomatic colonization to dissemination and disease in otherwise sterile sites remain poorly understood but are epidemiologically strongly linked to infection with respiratory viruses. In this report, we show that infection with influenza A virus and treatment with the resulting host signals (febrile-range temperatures, norepinephrine, extracytoplasmic ATP, and increased nutrient availability) induce the release of bacteria from biofilms in a newly developed biofilm model on live epithelial cells both in vitro and during in vivo colonization. These dispersed bacteria have distinct phenotypic properties different from those of both biofilm and broth-grown, planktonic bacteria, with the dispersed population showing differential virulence gene expression characteristics resulting in a significantly increased ability to disseminate and cause infection of otherwise sterile sites, such as the middle ear, lungs, and bloodstream. The results offer novel and important insights into the role of interkingdom signaling between microbe and host during biofilm dispersion and transition to acute disease. IMPORTANCE This report addresses the mechanisms involved in transition from pneumococcal asymptomatic colonization to disease. In this study, we determined that changes in the nasopharyngeal environment result in the release of bacteria from colonizing biofilms with a gene expression and virulence phenotype different not only from that of colonizing biofilm bacteria but also from that of the broth-grown planktonic bacteria commonly used for pathogenesis studies. The work importantly also identifies specific host factors responsible for the release of bacteria and their changed phenotype. We show that these interkingdom signals are recognized by bacteria and are induced by influenza virus infection, which is epidemiologically strongly associated with transition to secondary pneumococcal disease. As virus infection is a common inducer of transition to disease among species occupying the nasopharynx, the results of this study may provide a basis for better understanding of the signals involved in the transition from colonization to disease in the human nasopharynx. This report addresses the mechanisms involved in transition from pneumococcal asymptomatic colonization to disease. In this study, we determined that changes in the nasopharyngeal environment result in the release of bacteria from colonizing biofilms with a gene expression and virulence phenotype different not only from that of colonizing biofilm bacteria but also from that of the broth-grown planktonic bacteria commonly used for pathogenesis studies. The work importantly also identifies specific host factors responsible for the release of bacteria and their changed phenotype. We show that these interkingdom signals are recognized by bacteria and are induced by influenza virus infection, which is epidemiologically strongly associated with transition to secondary pneumococcal disease. As virus infection is a common inducer of transition to disease among species occupying the nasopharynx, the results of this study may provide a basis for better understanding of the signals involved in the transition from colonization to disease in the human nasopharynx.

Recombinant influenza virus vaccines based on hemagglutinin (HA) hold the potential to accelerate production timelines and improve efficacy relative to traditional egg-based platforms. Here, we assess a vaccine adjuvant system comprised of immunogenic liposomes that spontaneously convert soluble antigens into a particle format, displayed on the bilayer surface. When trimeric H3 HA was presented on liposomes, antigen delivery to macrophages was improved in vitro, and strong functional antibody responses were induced following intramuscular immunization of mice. Protection was conferred against challenge with a heterologous strain of H3N2 virus, and naive mice were also protected following passive serum transfer. When admixed with the particle-forming liposomes, immunization reduced viral infection severity at vaccine doses as low as 2 ng HA, highlighting dose-sparing potential. In ferrets, immunization induced neutralizing antibodies that reduced the upper respiratory viral load upon challenge with a more modern, heterologous H3N2 viral strain. To demonstrate the flexibility and modular nature of the liposome system, 10 recombinant surface antigens representing distinct influenza virus strains were bound simultaneously to generate a highly multivalent protein particle that with 5 ng individual antigen dosing induced antibodies in mice that specifically recognized the constituent immunogens and conferred protection against heterologous H5N1 influenza virus challenge. Taken together, these results show that stable presentation of recombinant HA on immunogenic liposome surfaces in an arrayed fashion enhances functional immune responses and warrants further attention for the development of broadly protective influenza virus vaccines.

The perovskite ABO 3 structure serves as the foundation for diverse functional and quantum materials, yet its applications are hindered by challenges in control of film stoichiometry and the precise construction of interfaces, particularly compared to conventional semiconductors. While a layer-by-layer growth mode is frequently cited, we demonstrate that many transition-metal perovskite oxides self-assemble via an energetically favorable layer-inversion mechanism. This phenomenon can be strategically exploited to fine-tune stoichiometry and surface termination at any point during growth. Layer inversion produces consistent behavior in electron diffraction rocking curves and diffracted-beam intensity oscillations during alternating A- and B-site shuttered growth across various polar and nonpolar surfaces. We introduce a model that accurately interprets these oscillations, enabling an entirely in situ method for precise relative and absolute calibration of multielemental A- and B-site fluxes at the percent level. This approach is successfully applied to the growth of a single-phase high-entropy oxide film. The authors report on a method for precise control of stoichiometry and surface termination during thin-film growth of a wide range of perovskite ABO 3 phases that exploits dynamic B-site layer inversion seen in the in situ electron diffraction.

Neutrophils are armed with both oxidant-dependent and -independent pathways for killing pathogens. Activation of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase constitutes an emergency response to infectious threat and results in the generation of antimicrobial reactive oxidants. In addition, NADPH oxidase activation in neutrophils is linked to activation of granular proteases and generation of neutrophil extracellular traps (NETs). NETosis involves the release of nuclear and granular components that can target extracellular pathogens. NETosis is activated during microbial threat and in certain conditions mimicking sepsis, and can result in both augmented host defense and inflammatory injury. In contrast, apoptosis, the physiological form of neutrophil death, not only leads to non-inflammatory cell death but also contributes to alleviate inflammation. Although there are significant gaps in knowledge regarding the specific contribution of NETs to host defense, we speculate that the coordinated activation of NADPH oxidase and NETosis maximizes microbial killing. Work in engineered mice and limited patient experience point to varying susceptibility of bacterial and fungal pathogens to NADPH oxidase versus NET constituents. Since reactive oxidants and NET constituents can injure host tissue, it is important that these pathways be tightly regulated. Recent work supports a role for NETosis in both acute lung injury and in autoimmunity. Knowledge gained about mechanisms that modulate NETosis may lead to novel therapeutic approaches to limit inflammation-associated injury.

In the growing field of spintronic devices incorporating antiferromagnetic materials, control of the domain configuration and Néel axis orientation is critical for technological implementations. Here we show by X-ray magnetic linear dichroism in photoelectron emission microscopy how antiferromagnetic properties of LaFeO 3 (LFO) thin films can be tailored through epitaxial strain. LFO films were grown via molecular beam epitaxy with precise stoichiometric control, using substrates that span a range of strain states—from compressive to tensile—and crystal symmetries, including different crystallographic orientations. First, we show that epitaxial strain dictates the Néel axis orientation, shifting it from completely in-plane under compressive strain to completely out-of-plane under tensile strain, regardless of the substrate crystal symmetry. Second, we find that LFO films grown on cubic substrates exhibit a fourfold distribution of antiferromagnetic domains, but can be controlled by varying the substrate miscut, while those on orthorhombic substrates, regardless of strain state, form large-scale monodomains, a highly desirable feature for spintronic applications. Precise control over antiferromagnetic domain configurations and Néel axis orientation is essential for technological advancement of spintronic devices. Here, the authors use epitaxial strain to tailor the magnetic properties of LaFeO 3 thin films, demonstrating a crystal engineering approach which may have much wider applicability.

Spin degree of freedom generally plays an important role in unconventional superconductivity. In many of the iron-based compounds, superconductivity is found in close proximity to long-range antiferromagnetic order, whereas monolayer FeSe grown on SrTiO3, with enhanced superconductivity, exhibits no magnetic or nematic ordering. Here we grow monolayer and multilayer FeSe on antiferromagnetic EuTiO3(001) layers, in an effort to introduce a spin polarization in proximity to the superconductivity of FeSe. By X-ray magnetic dichroism, we observe an antiferromagnet–ferromagnet switching on Eu and Ti sites in EuTiO3 driven by the applied magnetic field, with no concomitant spin polarization on the Fe site of FeSe. Transport measurements show enhanced superconductivity of monolayer FeSe on EuTiO3 with a transition temperature of ~30 K. The band structure revealed by photoemission spectroscopy is analogous to that of FeSe/SrTiO3. Our work creates a platform for the interplay of spin and unconventional superconductivity in the two-dimensional limit.

Pro-inflammatory M1 macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C > U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections in normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of nonsynonymous RNA editing alters a highly-conserved amino acid in THOC5, which encodes a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-α, IL-1β and IL-6 cytokine secretion, and increases glycolysis. These results show a key role of APOBEC3A cytidine deaminase in transcriptomic and functional polarization of M1 macrophages.Alqassim et al find that RNA editing, known to be induced by IFN-1 in macrophages by the enzyme APOBEC3A, is required for the transcriptional, pro-inflammatory and metabolic responses that drive M1 macrophage polarization. APOBEC3A-mediated editing is also induced by IFN-1 exposure in tumor-associated macrophages isolated from ovarian cancer-related ascites fluid, pointing to a wide role for APOBEC3A in macrophages.

Interlayer excitons in solid‐state systems have emerged as candidates for realizing novel platforms ranging from excitonic transistors and optical qubits to exciton condensates. Interlayer excitons have been discovered in 2D transition metal dichalcogenides, with large exciton binding energies and the ability to form various van der Waals heterostructures. Here, an oxide system consisting of a single unit cell of Mg2TiO4 on MgO (001) is proposed as a platform for hosting interlayer excitons. Using a combination of density functional theory (DFT) calculations, molecular beam epitaxy growth, and in situ crystal truncation rod measurements, it is shown that the Mg2TiO4‐MgO interface can be precisely controlled to yield an internal electric field suitable for hosting interlayer excitons. The atoms in the polar Mg2TiO4 layers are observed to be displaced to reduce polarity at the interface with the non‐polar MgO (001) surface. Such polarity‐driven atomic displacements strongly affect electrostatics of the film and the interface, resulting in localization of filled and empty band‐edge states in different layers of the Mg2TiO4 film. The DFT calculations suggest that the electronic structure is favorable for localization of photoexcited electrons in the bottom layer and holes in the top layer, which may bind to form interlayer exciton states. 2D Mg2TiO4 on MgO (001) is proposed as a transition metal oxide system for hosting interlayer excitons. Theoretical calculations predict localization of electrons and holes in the bottom and top Mg2TiO4 layers respectively, which can bind to form interlayer excitons. The Mg2TiO4 thin films are grown using molecular beam epitaxy and their crystal structure is determined with synchrotron X‐ray experiments.

Two-dimensional electron gas systems (2DEGs) generated at the oxide interfaces that exhibit rich physics phenomena opened up an era for oxide-based electronics, photonics, and spintronics. The recent discovery of superconductivity plus the strong spin-orbital coupling naturally existing in the 2DEGs of KTaO3 (KTO) made KTO an exciting platform for the interplay of the electronic and spin degrees of freedom to create exotic physical properties. By directly placing KTO’s 2DEGs next to another strongly-correlated oxide with nontrivial topological nodes, we reveal the anomalous effects which were induced by the topological states in the electronic transport properties of the KTO’s 2DGEs, due to the electronic reconstruction caused by the proximity effect. This adds an additional prospect to the functions of KTO heterostructures.

Lung contusion (LC), commonly observed in patients with thoracic trauma is a leading risk factor for development of acute lung injury/acute respiratory distress syndrome. Previously, we have shown that CC chemokine ligand (CCL)-2, a monotactic chemokine abundant in the lungs, is significantly elevated in LC. This study investigated the nature of protection afforded by CCL-2 in acute lung injury/acute respiratory distress syndrome during LC, using rats and CC chemokine receptor (CCR) 2 knockout (CCR2(-/-)) mice. Rats injected with a polyclonal antibody to CCL-2 showed higher levels of albumin and IL-6 in the bronchoalveolar lavage and myeloperoxidase in the lung tissue after LC. Closed-chest bilateral LC demonstrated CCL-2 localization in alveolar macrophages (AMs) and epithelial cells. Subsequent experiments performed using a murine model of LC showed that the extent of injury, assessed by pulmonary compliance and albumin levels in the bronchoalveolar lavage, was higher in the CCR2(-/-) mice when compared with the wild-type (WT) mice. We also found increased release of IL-1β, IL-6, macrophage inflammatory protein-1, and keratinocyte chemoattractant, lower recruitment of AMs, and higher neutrophil infiltration and phagocytic activity in CCR2(-/-) mice at 24 hours. However, impaired phagocytic activity was observed at 48 hours compared with the WT. Production of CCL-2 and macrophage chemoattractant protein-5 was increased in the absence of CCR2, thus suggesting a negative feedback mechanism of regulation. Isolated AMs in the CCR2(-/-) mice showed a predominant M1 phenotype compared with the predominant M2 phenotype in WT mice. Taken together, the above results show that CCL-2 is functionally important in the down-modulation of injury and inflammation in LC.