Preferential Secretion of Thymic Stromal Lymphopoietin (TSLP) by Terminally Differentiated Esophageal Epithelial Cells: Relevance to Eosinophilic Esophagitis (EoE)

Eosinophilic esophagitis (EoE) is a chronic Th2 and food antigen-mediated disease characterized by esophageal eosinophilic infiltration. Thymic stromal lymphopoetin (TSLP), an epithelial derived cytokine which bridges innate and Th2-type adaptive immune responses in other allergic conditions, is overexpressed in esophageal biopsies of EoE subjects. However, the triggers of TSLP expression in the esophageal epithelium are unknown. The objective of the current study was to characterize TSLP expression in human esophageal epithelium in EoE in vivo and to determine the role of food antigens upon epithelial TSLP expression in vitro. Using immunohistochemistry (IHC), we localized TSLP in esophageal biopsies of active EoE (≥15 eos/hpf), inactive EoE (<15 eos/hpf) and non-EoE control subjects, and found that TSLP expression was restricted to the differentiated suprabasal layer of the epithelium in actively inflamed EoE biopsies. Consistent with these results in vivo, inducible TSLP protein secretion was higher in CaCl₂ differentiated telomerase-immortalized esophageal epithelial cells (EPC2-hTERT) compared to undifferentiated cells of the basal phenotype, following stimulation with the TLR3 ligand poly(I:C). To determine whether food antigens could directly induce epithelial TSLP secretion, differentiated and undifferentiated primary esophageal epithelial cells from EoE and non-EoE subjects were challenged with food antigens clinically relevant to EoE: Chicken egg ovalbumin (OVA), wheat, and milk proteins beta-lactoglobulin (blg) and beta-casein. Food antigens failed to induce TSLP secretion by undifferentiated cells; in contrast, only OVA induced TSLP secretion in differentiated epithelial cells from both EoE and control cell lines, an effect abolished by budesonide and NF-κb inhibition. Together, our study shows that specific food antigens can trigger innate immune mediated esophageal TSLP secretion, suggesting that esophageal epithelial cells at the barrier surface may play a significant role in the pathogenesis of EoE by regulating TSLP expression.     

Factors that Influence the Formation and Stability of Thin,Cryo-EM Specimens

Poor consistency of the ice thickness from one area of a cryo-electron microscope (cryo-EM) specimen grid to another, from one grid to the next, and from one type of specimen to another, motivates a reconsideration of how to best prepare suitably thin specimens. Here we first review the three related topics of wetting, thinning, and stability against dewetting of aqueous films spread over a hydrophilic substrate. We then suggest that the importance of there being a surfactant monolayer at the air-water interface of thin, cryo-EM specimens has been largely underappreciated. In fact, a surfactant layer (of uncontrolled composition and surface pressure) can hardly be avoided during standard cryo-EM specimen preparation. We thus suggest that better control over the composition and properties of the surfactant layer may result in more reliable production of cryo-EM specimens with the desired thickness.     

Molecular basis of ion permeability in a voltage‐gated sodium channel

Voltage‐gated sodium channels are essential for electrical signalling across cell membranes. They exhibit strong selectivities for sodium ions over other cations, enabling the finely tuned cascade of events associated with action potentials. This paper describes the ion permeability characteristics and the crystal structure of a prokaryotic sodium channel, showing for the first time the detailed locations of sodium ions in the selectivity filter of a sodium channel. Electrostatic calculations based on the structure are consistent with the relative cation permeability ratios (Na⁺ ≈ Li⁺ ≫ K⁺, Ca²⁺, Mg²⁺) measured for these channels. In an E178D selectivity filter mutant constructed to have altered ion selectivities, the sodium ion binding site nearest the extracellular side is missing. Unlike potassium ions in potassium channels, the sodium ions in these channels appear to be hydrated and are associated with side chains of the selectivity filter residues, rather than polypeptide backbones.     

The Emergence of Synaesthesia in a Neuronal Network Model via Changes in Perceptual Sensitivity and Plasticity

Synaesthesia is an unusual perceptual experience in which an inducer stimulus triggers a percept in a different domain in addition to its own. To explore the conditions under which synaesthesia evolves, we studied a neuronal network model that represents two recurrently connected neural systems. The interactions in the network evolve according to learning rules that optimize sensory sensitivity. We demonstrate several scenarios, such as sensory deprivation or heightened plasticity, under which synaesthesia can evolve even though the inputs to the two systems are statistically independent and the initial cross-talk interactions are zero. Sensory deprivation is the known causal mechanism for acquired synaesthesia and increased plasticity is implicated in developmental synaesthesia. The model unifies different causes of synaesthesia within a single theoretical framework and repositions synaesthesia not as some quirk of aberrant connectivity, but rather as a functional brain state that can emerge as a consequence of optimising sensory information processing.     

关于（荒野）殖民化

由于人类体验自然的渴望日益增长,在政治和实践层面,在城市中提供接触自然的机会显得越来越必要。关于“城市荒野”的思想和规划旨在提供一种特殊的自然体验。鉴于不同荒野思想之间存在冲突,风景园林师必须设法了解已有的荒野认知及其含义。通过 3 个荒野类别—“未知荒野”“特定荒野”和“过程荒野”,探讨发展千年的荒野理念,并提出“殖民化”（colonisations）概念作为理解荒野理念发展的一个关键。自然过程伴随着动植物对空间的殖民,而人类进入和占有空间的殖民过程则包含生理、心理和精神 3 个层面的内容。空间命名是一种特殊的、具有精神和象征意味的殖民化形式。例如,人类在城市中发现野生植被,称其为“野性自然”或“城市荒野”。然而,如今大多数（尤其官方）的荒野定义中均排除了人类干扰：一旦被殖民,真正的荒野就不复存在。科学研究对自然过程的殖民化已取得很多成果,但对于人类有关自然和荒野的认知和态度了解并不多。对于风景园林师来说,这有助于更好地理解如何“基于自然进行设计和建造”,对创造令人满意的景观也非常重要。探讨与“城市荒野”有关的论述、规划和设计观点及思想。 由于人类体验自然的渴望日益增长,在政治和实践层面,在城市中提供接触自然的机会显得越来越必要。关于“城市荒野”的思想和规划旨在提供一种特殊的自然体验。鉴于不同荒野思想之间存在冲突,风景园林师必须设法了解已有的荒野认知及其含义。通过 3 个荒野类别—“未知荒野”“特定荒野”和“过程荒野”,探讨发展千年的荒野理念,并提出“殖民化”（colonisations）概念作为理解荒野理念发展的一个关键。自然过程伴随着动植物对空间的殖民,而人类进入和占有空间的殖民过程则包含生理、心理和精神 3 个层面的内容。空间命名是一种特殊的、具有精神和象征意味的殖民化形式。例如,人类在城市中发现野生植被,称其为“野性自然”或“城市荒野”。然而,如今大多数（尤其官方）的荒野定义中均排除了人类干扰：一旦被殖民,真正的荒野就不复存在。科学研究对自然过程的殖民化已取得很多成果,但对于人类有关自然和荒野的认知和态度了解并不多。对于风景园林师来说,这有助于更好地理解如何“基于自然进行设计和建造”,对创造令人满意的景观也非常重要。探讨与“城市荒野”有关的论述、规划和设计观点及思想。     

Genome‐based estimates of fungal rDNA copy number variation across phylogenetic scales and ecological lifestyles

Ribosomal DNA (rDNA) copy number variation (CNV) has major physiological implications for all organisms, but how it varies for fungi, an ecologically ubiquitous and important group of microorganisms, has yet to be systemically investigated. Here, we examine rDNA CNV using an in silico read depth approach for 91 fungal taxa with sequenced genomes and assess copy number conservation across phylogenetic scales and ecological lifestyles. rDNA copy number varied considerably across fungi, ranging from an estimated 14 to 1,442 copies (mean = 113, median = 82), and copy number similarity was inversely correlated with phylogenetic distance. No correlations were found between rDNA CNV and fungal trophic mode, ecological guild or genome size. Taken together, these results show that like other microorganisms, fungi exhibit substantial variation in rDNA copy number, which is linked to their phylogeny in a scale‐dependent manner.     

Structural Basis for CD96 Immune Receptor Recognition of Nectin-like Protein-5, CD155

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