Atomic-Scale Scanning of Domain Network in the Ferroelectric HfO2 Thin Film.

Ferroelectric HfO2-based thin films have attracted much interest in the utilization of ferroelectricity at the nanoscale for next-generation electronic devices. However, the structural origin and stabilization mechanism of the ferroelectric phase are not understood because the film is typically nanocrystalline with active yet stochastic ferroelectric domains. Here, electron microscopy is used to map the in-plane domain network structures of epitaxially grown ferroelectric Y:HfO2 films in atomic resolution. The ferroelectricity is confirmed in free-standing Y:HfO2 films, allowing for investigating the structural origin for their ferroelectricity by 4D-STEM, high-resolution STEM, and iDPC-STEM. At the grain boundaries of <111>-oriented Pca21 orthorhombic grains, a high-symmetry mixed-(R3m, Pnm21) phase is induced, exhibiting enhanced polarization due to in-plane compressive strain. Nanoscale Pca21 orthorhombic grains and their grain boundaries with mixed-(R3m, Pnm21) phases of higher symmetry cooperatively determine the ferroelectricity of the Y:HfO2 film. It is also found that such ferroelectric domain networks emerge when the film thickness is beyond a finite value. Furthermore, in-plane mapping of oxygen positions overlaid on ferroelectric domains discloses that polarization is suppressed at vertical domain walls, while it is active when domains are aligned horizontally with subangstrom domain walls. In addition, randomly distributed 180° charged domain walls are confined by spacer layers.

Pyronaridine Inhibited MUC5AC Mucin Gene Expression by Regulation of Nuclear Factor Kappa B Signaling Pathway in Human Pulmonary Mucoepidermoid Cells.

In this study, the potential effects of pyronaridine, an antimalarial agent, on airway MUC5AC mucin gene expression were investigated. The human pulmonary epithelial NCI-H292 cells were pretreated with pyronaridine for 30 min and then stimulated with phorbol 12-myristate 13-acetate (PMA) for 24 h. The effect of pyronaridine on the PMA-induced nuclear factor kappa B (NF-κB) signaling pathway was also examined. Pyronaridine inhibited glycoprotein production and mRNA expression of MUC5AC mucins induced by PMA through the inhibition of degradation of inhibitory kappa Bα and NF-κB p65 nuclear translocation. These results suggest that pyronaridine suppresses gene expression of mucin through regulation of the NF-κB signaling pathway in human pulmonary epithelial cells.

Plasmodium infection induces phenotypic, clonal, and spatial diversity among differentiating CD4+ T cells.

Naive CD4+ T cells must differentiate in order to orchestrate immunity to Plasmodium, yet understanding of their emerging phenotypes, clonality, spatial distributions, and cellular interactions remains incomplete. Here, we observe that splenic polyclonal CD4+ T cells differentiate toward T helper 1 (Th1) and T follicular helper (Tfh)-like states and exhibit rarer phenotypes not elicited among T cell receptor (TCR) transgenic counterparts. TCR clones present at higher frequencies exhibit Th1 skewing, suggesting that variation in major histocompatibility complex class II (MHC-II) interaction influences proliferation and Th1 differentiation. To characterize CD4+ T cell interactions, we map splenic microarchitecture, cellular locations, and molecular interactions using spatial transcriptomics at near single-cell resolution. Tfh-like cells co-locate with stromal cells in B cell follicles, while Th1 cells in red pulp co-locate with activated monocytes expressing multiple chemokines and MHC-II. Spatial mapping of individual transcriptomes suggests that proximity to chemokine-expressing monocytes correlates with stronger effector phenotypes in Th1 cells. Finally, CRISPR-Cas9 gene disruption reveals a role for CCR5 in promoting clonal expansion and Th1 differentiation. A database of cellular locations and interactions is presented: https://haquelab.mdhs.unimelb.edu.au/spatial_gui/.

CD4+ T cells display a spectrum of recall dynamics during re-infection with malaria parasites.

Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4+ T cell subsets remain unresolved. Here, we examine antigen-experienced CD4+ T cells during re-infection in mice, using scRNA-seq/TCR-seq and spatial transcriptomics. TCR transgenic TEM cells initiate rapid Th1/Tr1 recall responses prior to proliferating, while GC Tfh counterparts are refractory, with TCM/Tfh-like cells exhibiting modest non-proliferative responses. Th1-recall is a partial facsimile of primary Th1-responses, with no upregulated effector-associated genes being unique to recall. Polyclonal, TCR-diverse, CD4+ T cells exhibit similar recall dynamics, with individual clones giving rise to multiple effectors including highly proliferative Th1/Tr1 cells, as well as GC Tfh and Tfh-like cells lacking proliferative capacity. Thus, we show substantial diversity in recall responses mounted by multiple co-existing CD4+ T cell subsets in the spleen, and present graphical user interfaces for studying gene expression dynamics and clonal relationships during re-infection.

CHD7 variants associated with hearing loss and enlargement of the vestibular aqueduct.

Enlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants in SLC26A4. However, in European-Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles of SLC26A4. We tested for the presence of variants in CHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles of SLC26A4. In two families, NM_017780.4: c.3553A > G [p.(Met1185Val)] and c.5390G > C [p.(Gly1797Ala)] were detected as monoallelic CHD7 variants in patients with EVA. At least one subject from each family had additional signs or potential signs of CHARGE syndrome but did not meet diagnostic criteria for CHARGE. In silico modeling of these two missense substitutions predicted detrimental effects upon CHD7 protein structure. Consistent with a role of CHD7 in this tissue, Chd7 transcript and protein were detected in all epithelial cells of the endolymphatic duct and sac of the developing mouse inner ear. These results suggest that some CHD7 variants can cause nonsyndromic hearing loss and EVA. CHD7 should be included in DNA sequence analyses to detect pathogenic variants in EVA patients. Chd7 expression and mutant phenotype data in mice suggest that CHD7 contributes to the formation or function of the endolymphatic sac and duct.

Novel small molecule-mediated restoration of the surface expression and anion exchange activity of mutated pendrin causing Pendred syndrome and DFNB4.

Variants in SLC26A4 (pendrin) are the most common reasons for genetic hearing loss and vestibular dysfunction in East Asians. In patients with Pendred syndrome and DFNB4 (autosomal recessive type of genetic hearing loss 4), caused by variants in SLC26A4, the hearing function is residual at birth and deteriorates over several years, with no curative treatment for these disorders. In the present study, we revealed that a novel small molecule restores the expression and function of mutant pendrin. High-throughput screening of 54,000 small molecules was performed. We observed that pendrin corrector (PC2-1) increased the surface expression and anion exchange activity of p.H723R pendrin (H723R-PDS), the most prevalent genetic variant that causes Pendred syndrome and DFNB4. Furthermore, in endogenous H723R-PDS-expressing human nasal epithelial cells, PC2-1 significantly increased the surface expression of pendrin. PC2-1 exhibited high membrane permeability in vitro and high micromolar concentrations in the cochlear perilymph in vivo. In addition, neither inhibition of Kv11.1 activity in the human ether-a-go-go-related gene assay nor cell toxicity in the cell proliferation assay was observed at a high PC2-1 concentration (30 µM). These preclinical data support the hypothesis of the druggability of mutant pendrin using the novel corrector molecule PC2-1. In conclusion, PC2-1 may be a new therapeutic molecule for ameliorating hearing loss and treating vestibular disorders in patients with Pendred syndrome or DFNB4.

Synergistic Effect of Size-Tailored Structural Engineering and Postinterface Modification for Highly Efficient and Stable Dye-Sensitized Solar Cells.

Despite significant progress in device performance, dye-sensitized solar cells (DSSCs) continue to fall short of their theoretical potential. Moreover, research in recent years needs to pay more attention to improving the device fabrication process. To achieve the theoretical efficiency limit, it is crucial to optimize the interface between the dye and TiO2 nanoparticles in the entire device stack. Our study indicates that optimizing the structure or size of the coadsorbents and implementing a monolayer adsorption process can be an effective strategy to reduce charge recombination and enhance light-harvesting properties. Our research aims to develop a surface-coating adsorbent plan that controls the TiO2 nanoparticle interface to achieve the radiative limit of power conversion efficiency (PCE). Specifically, we utilized 2-thiophenecarboxylic acid (THCA) or chenodeoxycholic acid (CDCA) as postinterfacial surface-coating adsorbents. Our results demonstrate that this approach effectively achieves the desired PCE limit. Combined with the coadsorbent structure engineering and interface optimization, the device increased the packing area on the TiO2 nanoparticles' surface, reaching an improved PCE of over 13.17% under simulated sunlight (1.5G), which is the highest efficiency of a porphyrin single dye-based DSSC. In particular, this practical approach was also applied to a large-area DSSC with an area of 3 cm2, yielding a remarkable PCE of 9.04%. Furthermore, when applied to a polymer gel electrolyte, this novel approach recorded the highest PCE of 11.16% with a long-term operational stability of up to 1000 h for the quasi-solid-state DSSCs. Our research findings provide a promising avenue for achieving high-performance DSSCs with ease of access and demonstrate practical applications as alternatives to conventional power sources.

Systemic host inflammation induces stage-specific transcriptomic modification and slower maturation in malaria parasites.

Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm; whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute Plasmodium infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma. Metabolomic assessments confirmed substantial alterations to the plasma of LPS-conditioned and acutely infected mice, and identified a small number of candidate inhibitory metabolites. Finally, we confirmed rapid parasite responses to systemic host inflammation in vivo using parasite scRNA-seq, noting broad impairment in transcriptional activity and translational capacity specifically in trophozoites but not rings or schizonts. Thus, we provide evidence that systemic host inflammation rapidly triggered transcriptional alterations in circulating blood-stage Plasmodium trophozoites and predict candidate inhibitory metabolites in the plasma that may impair parasite maturation in vivo. IMPORTANCE Malaria parasites cyclically invade, multiply, and burst out of red blood cells. We found that a strong inflammatory response can cause changes to the composition of host plasma, which directly slows down parasite maturation. Thus, our work highlights a new mechanism that limits malaria parasite growth in the bloodstream.

Regulation of the Gene Expression of Airway MUC5AC Mucin through NF-κB Signaling Pathway by Artesunate, an Antimalarial Agent.

In this study, artesunate, an antimalarial agent, was investigated for its potential effect on the gene expression of airway MUC5AC mucin. The human pulmonary epithelial NCI-H292 cells were pretreated with artesunate for 30 min and then stimulated with phorbol 12-myristate 13-acetate (PMA), for the following 24 h. The effect of artesunate on PMA-induced nuclear factor kappa B (NF-kB) signaling pathway was also examined. Artesunate inhibited the glycoprotein production and mRNA expression of MUC5AC mucins, induced by PMA through the inhibition of degradation of inhibitory kappa Bα (IkBα) and NF-kB p65 nuclear translocation. These results suggest artesunate suppresses the gene expression of mucin through regulation of NF-kB signaling pathway, in human pulmonary epithelial cells.