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Common γ chain (γc) cytokine receptors, including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, are activated upon engagement with a common γc receptor (CD132) by concomitant binding of their ectodomains to an interleukin. In this work, we find that direct interactions between the transmembrane domains (TMDs) of both the γc and the interleukin receptors (ILRs) are also required for receptor activation. Moreover, the same γc TMD can specifically recognize multiple ILR TMDs of diverse sequences within the family. Heterodimer structures of γc TMD bound to IL-7 and IL-9 receptor TMDs—determined in a lipid bilayer–like environment by nuclear magnetic resonance spectroscopy—reveal a conserved knob-into-hole mechanism of recognition that mediates receptor sharing within the membrane. Thus, signaling in the γc receptor family requires specific heterotypic interactions of the TMDs. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a worldwide chronic inflammatory lung disease, and influenza A virus (IAV) infection is a common cause of acute exacerbations of COPD (AECOPD). Therefore, targeting viral infections represents a promising strategy to prevent the occurrence and development of inflammatory flare ups in AECOPD. Jianpiyifei II (JPYFII) is a traditional herbal medicine used in China to treat patients with COPD, and its clinical indications are not well understood. However, investigation of the anti-inflammatory effects and underlying mechanism using an animal model of smoking have been reported in a previous study by our group. In addition, some included herbs, such as Radix astragali and Radix aupleuri, were reported to exhibit antiviral effects. Therefore, the aim of the present study was to investigate whether JPYFII formulation relieved acute inflammation by clearing the IAV in a mouse model that was exposed to cigarette smoke experimentally. JPYFII formulation treatment during smoke exposure and IAV infection significantly reduced the number of cells observed in bronchoalveolar lavage fluid (BALF), expression of proinflammatory cytokines, chemokines, superoxide production, and viral load in IAV-infected and smoke-exposed mice. However, JPYFII formulation treatment during smoke exposure alone did not reduce the number of cells in BALF or the expression of Il-6, Tnf-a, and Il-1?. The results demonstrated that JPYFII formulation exerted an antiviral effect and reduced the exacerbation of lung inflammation in cigarette smoke (CS)-exposed mice infected with IAV. Our results suggested that JPYFII formulation could potentially be used to treat patients with AECOPD associated with IAV infection. [ABSTRACT FROM AUTHOR]

Hair cells are sensory receptors for the auditory and vestibular system in vertebrates. The transcription factor Atohl is both necessary and sufficient for the differentiation of hair cells, and is strongly upregulated during hair-cell regeneration in nonmammalian vertebrates. To identify genes involved in hair cell development and function, we performed RNA-seq profiling of purified Atoh1-expressing hair cells from the neonatal mouse cochlea. We identified >600 enriched transcripts in cochlear hair cells, of which 90% have not been previously shown to be expressed in hair cells. We identified 233 of these hair cell genes as candidates to be directly regulated by Atoh1 based on the presence of Atoh1 binding sites in their regulatory regions and by analyzing Atoh1 ChIP-seq datasets from the cerebellum and small intestine. We confirmed 10 of these genes as being direct Atoh1 targets in the cochlea by ChIP-PCR. The identification of candidate Atoh1 target genes is a first step in identifying gene regulatory networks for hair-cell development and may inform future studies on the potential role ofAtoh1 in mammalian hair cell regeneration. [ABSTRACT FROM AUTHOR]

Atonal homologl (A tohl) encodes a basic helix-loop-helix protein that is the first transcription factor to be expressed in differentiating hair cells. Previous work suggests that expression of Atohl in prosensory precursors is necessary for the differentiation and survival of hair cells, but it is not clear whether A toh 1 is required exclusively for these processes, or whether it regulates other functions later during hair cell maturation. We used EGFP-tagged Atohl knock-in mice to demonstrate for the first time that Atohl protein is expressed in hair cell precursors several days before the appearance of differentiated markers, but not in the broad pattern expected of a proneural gene. We conditionally deleted A tohl at different points in hair cell development and observe a rapid onset of hair cell defects, suggesting that the Atoh 1 protein is unstable in differentiating hair cells and is necessary through an extended phase of their differentiation. Conditional deletion of Atohl reveals multiple functions in hair cell survival, maturation of stereociliary bundles, and auditory function. We show the presence of distinct critical periods for A tohl in each of these functions, suggesting that A tohl may be directly regulating many aspects of hair cell function. Finally, we show that the supporting cell death that accompanies loss of Atohl in hair cells is likely caused by the abortive frans-differentiation of supporting cells into hair cells. Together our data suggest that Atohl regulates multiple aspects of hair cell development and function. [ABSTRACT FROM AUTHOR]

In this work, the band assignment for the vibration mode of the functional groups contained in α-tocopherol (aT) molecules was analyzed entirely for the first time using their normal Raman spectra (NRS), density functional theory (DFT) calculations, and potential energy distributions (PED). The bands obtained through the theory calculation method were in accordance with experimentally observed values. The surface-enhanced Raman scattering (SERS) spectra of aT adsorbed on nanoparticles were studied in gold colloidal solutions and on modified gold substrates. Some crucial differences were observed in the SERS spectra of the aT molecules adsorbed on these two substrates, indicating that the behavior of aT adsorbed on gold colloids was different from that of aT on the modified gold substrate. The aT molecules probably lie flat on the surfaces of the gold nanoparticles through the ring in the gold colloidal solution, whereas they stand with a certain angle on the gold surfaces of the modified substrate. Furthermore, the concentration dependence of SERS spectra of aT is characterized by variation of the enhanced intensity of the bands, primarily suggesting that the adsorption behavior of the aT molecules adsorbed on the gold nanoparticles surface is changed with different concentrations. With the concentration around 7.5 × 10−2mol/L, the sub-monolayer mode, and more aT molecules allowed to lie on the gold surface, then Raman signals are greatly enhanced in the SERS spectrum. [ABSTRACT FROM AUTHOR]

The morphology is the consequence of evolution and adaptation. Escherichia coli is rod-shaped bacillus with regular dimension of about 1.5 μm long and 0.5 μm wide. Many shape-related genes have been identified and used in morphology engineering of this bacteria. However, little is known about if specific metabolism and metal irons could modulate bacteria morphology. Here in this study, we discovered filamentous shape change of E. coli cells overexpressing pigeon MagR, a putative magnetoreceptor and extremely conserved iron-sulfur protein. Comparative transcriptomic analysis strongly suggested that the iron metabolism change and iron accumulation due to the overproduction of MagR was the key to the morphological change. This model was further validated, and filamentous morphological change was also achieved by supplement E. coli cells with iron in culture medium or by increase the iron uptake genes such as entB and fepA. Our study extended our understanding of morphology regulation of bacteria, and may also serves as a prototype of morphology engineering by modulating the iron metabolism. [ABSTRACT FROM AUTHOR]

Reprogramming of the cochlea with hair-cell-specific transcription factors such as ATOH1 has been proposed as a potential therapeutic strategy for hearing loss. ATOH1 expression in the developing cochlea can efficiently induce hair cell regeneration but the efficiency of hair cell reprogramming declines rapidly as the cochlea matures. We developed Cre-inducible mice to compare hair cell reprogramming with ATOH1 alone or in combination with two other hair cell transcription factors, GFI1 and POU4F3. In newborn mice, all transcription factor combinations tested produced large numbers of cells with the morphology of hair cells and rudimentary mechanotransduction properties. However, 1 week later, only a combination of ATOH1, GFI1 and POU4F3 could reprogram non-sensory cells of the cochlea to a hair cell fate, and these new cells were less mature than cells generated by reprogramming 1 week earlier. We used scRNA-seq and combined scRNA-seq and ATAC-seq to suggest at least two impediments to hair cell reprogramming in older animals. First, hair cell gene loci become less epigenetically accessible in non-sensory cells of the cochlea with increasing age. Second, signaling from hair cells to supporting cells, including Notch signaling, can prevent reprogramming of many supporting cells to hair cells, even with three hair cell transcription factors. Our results shed light on the molecular barriers that must be overcome to promote hair cell regeneration in the adult cochlea. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, autophagy is a highly conserved self-digestion process to promote cell survival in response to nutrient starvation and other metabolic stresses. Autophagy is regulated by cell signalling such as the mTOR (mammalian target of rapamycin) pathway. However, the significance of autophagy in modulation of signal transduction is unclear. Here we show that autophagy negatively regulates Wnt signalling by promoting Dishevelled (Dvl) degradation. Von Hippel–Lindau protein-mediated ubiquitylation is critical for the binding of Dvl2 to p62, which in turn facilitates the aggregation and the LC3-mediated autophagosome recruitment of Dvl2 under starvation; the ubiquitylated Dvl2 aggregates are ultimately degraded through the autophagy–lysosome pathway. Moreover, a reverse correlation between Dvl expression and autophagy is observed in late stages of colon cancer development, indicating that autophagy may contribute to the aberrant activation of Wnt signalling in tumour formation. [ABSTRACT FROM AUTHOR]