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Endothelial cell senescence is the main risk factor contributing to vascular dysfunction and the progression of aging-related cardiovascular diseases. However, the relationship between endothelial cell metabolism and endothelial senescence remains unclear. The present study provides novel insight into fatty acid metabolism in the regulation of endothelial senescence. In the replicative senescence model and H2O2-induced premature senescence model of primary cultured human umbilical vein endothelial cells (HUVECs), fatty acid oxidation (FAO) was suppressed and fatty acid profile was disturbed, accompanied by downregulation of proteins associated with fatty acid uptake and mitochondrial entry, in particular the FAO rate-limiting enzyme carnitine palmitoyl transferase 1A (CPT1A). Impairment of fatty acid metabolism by silencing CPT1A or CPT1A inhibitor etomoxir facilitated the development of endothelial senescence, as implied by the increase of p53, p21, and senescence-associated β-galactosidase, as well as the decrease of EdU-positive proliferating cells. In the contrary, rescue of FAO by overexpression of CPT1A or supplement of short chain fatty acids (SCFAs) acetate and propionate ameliorated endothelial senescence. In vivo, treatment of acetate for 4 weeks lowered the blood pressure and alleviated the senescence-related phenotypes in aortas of Ang II-infused mice. Mechanistically, fatty acid metabolism regulates endothelial senescence via acetyl-coenzyme A (acetyl-CoA), as implied by the observations that suppression of acetyl-CoA production using the inhibitor of ATP citrate lyase NDI-091143 accelerated senescence of HUVECs and that supplementation of acetyl-CoA prevented H2O2-induced endothelial senescence. Deficiency of acetyl-CoA resulted in alteration of acetylated protein profiles which are associated with cell metabolism and cell cycle. These findings thus suggest that improvement of fatty acid metabolism might ameliorate endothelial senescence-associated cardiovascular diseases.

Although consumers generally accept and care about environmental issues, consumers have not adjusted their behavior accordingly. Based on the diamond model theory, this study proposes and tests the direct impact of personal green commitments on low-carbon travel motivation and constraint, and the possibility of subsequent low-carbon travel intention. According to the results of 358 valid questionnaire surveys, this study shows that green commitments positively affect the low-carbon travel motivation and intention, while negatively affecting the low-carbon travel constraint. The low-carbon travel motivation has some mediating effects. The research results can be used as a reference by relevant managers of the tourism industry to make changes in the content of travel services that are more suitable for specific populations.

The spinel-type LiMn2O4 is a promising candidate as cathode material for rechargeable Li-ion batteries due to its good thermal stability and safety. Experimentally, it is observed that in this compound there occur the structural phase transitions from cubic ( F d 3 ¯ m ) to tetragonal (I41/amd) phase at slightly below room temperature. To understand the phase transition mechanism, we compare the Gibbs free energy between cubic phase and tetragonal phase by including the configurational entropy. Our results show that the configurational entropy contributes substantially to the stability of the cubic phase at room temperature due to the disordered Mn3+/Mn4+ distribution as well as the orientation of the Jahn–Teller elongation of the Mn3+O6 octahedron in the the spinel phase. Meanwhile, the phase transition temperature is predicted to be 267.8 K, which is comparable to the experimentally observed temperature. These results serve as a good complement to the experimental study, and are beneficial to the improving of the electrochemical performance of LiMn2O4 cathode.

Objective: The associations between climate variables and diseases such as respiratory infections, influenza, pediatric seizure, and gastroenteritis have been long appreciated. Infection is the main reason for acute otitis media (AOM) incidence. However, few previous studies explored the correlation between climatic parameters and AOM infections. The most important meteorological factors, temperature, relative humidity, and fine particulate matter (PM2.5), were included in this study. We studied the relationship between these meteorological factors and the AOM visits. Materials and Methods: It was a retrospective cross-sectional study. A linear correlation and a linear regression model were used to explore the AOM visits and meteorological factors. Results: A total of 7075 emergency department visits for AOM were identified. Relative humidity was found an independent risk factor for the AOM visits in preschool children (regression coefficient = −10.841Conclusion: Humidity may have a significant inverse impact on the incidence of AOM in preschool-age children.

Objectives To identify genes that are related to delayed endolymphatic hydrops (DEH) in patients by RNA-Seq analysis. Design Observational study. Setting Eye & ENT Hospital, Fudan University (Shanghai, China). Participants We collected the entire vestibular system from four patients with DEH who underwent labyrinthectomy. Three control samples were collected from patients with acoustic neuroma or facial neuroma treated via the translabyrinthine approach. High-throughput RNA-Seq analysis was performed to investigate gene expression in the pathological vestibular system. Main outcome measures Our bioinformatics analysis identified 17 genes that were upregulated and eight genes that were downregulated in patients with DEH compared to the controls. Results The altered gene expression profile suggested that DEH is closely related to neuropathy and autoimmune disease. In addition, many of the differentially regulated genes were involved in cell adhesion, suggesting a role of cell adhesion in DEH. Immunofluorescence analysis confirmed the expression of PMP2 and CLDN19 in the cytoplasm of hair cells and scattered expression of MPZ at cell junctions. The protein expression levels were higher in specimens from patients with Meniere's disease and DEH compared to controls. Conclusions The protein expression profile of vestibular organs in patients with endolymphatic hydrops exhibited a degree of similarity to that of Meniere's disease. Endolymphatic hydrops is characterized by autoimmune abnormalities. DEH and Meniere's disease are likely to be different manifestations of the same disease, with disparate clinical symptoms. RNA-Seq is a useful analytical tool to characterise the vestibular pathology based on its transcriptome.

Planar cell polarity (PCP) signalling specifies the orientation of epithelial cells and regulates directional beating of motile cilia of multiciliated epithelial cells. Clinically, defects in cilia function are associated with nasopharyngeal symptoms. The polarity of the nasopharyngeal epithelium is poorly understood. Here, we demonstrated PCP in the nasopharyngeal epithelium. Multiciliated cells (MCCs) were uniformly aligned with their long axis parallel to the tissue axis of the nasopharynx (NP). In addition, PCP proteins exhibited an asymmetrical localisation between adjacent cells. Motile cilia were uniformly aligned in the same direction within both individual cells and neighbouring cells, which manifested as cilial polarity in MCCs. Mutation of Vangl2, a mammalian homologue of the Drosophila PCP gene, resulted in significant disruption of the orientation of epithelial cells. Finally, keratin-5-positive basal cells constantly replenished the luminal ciliated cells; the new dynamic ciliated cells were also oriented parallel to the tissue axis. These results indicate a role for the PCP pathway in the uniform orientation of dynamically replenished epithelial cells in the NP.

Mucous cell metaplasia/hyperplasia in the middle ear epithelium is associated with the occurrence of otitis media with effusion during infections. However, the mechanism by which Notch signaling regulates cell fate in the middle ear epithelium is unclear. The aim of the present study was to elucidate this mechanism by investigating the localization of Notch receptors, such as Notch1 and Notch2, and Notch ligands, such as Jagged1, in the normal mouse middle ear epithelium (NMMEE) using immunofluorescence. Furthermore, the mRNA expression levels of Notch receptors and ligands were evaluated using reverse transcription polymerase chain reaction (PCR). The effects of the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT) on epithelial cell proliferation were determined using 5-ethynyl-2′-deoxyuridine (EdU) staining and immunofluorescence staining of the apoptosis marker caspase-3 and the epithelial proliferation marker pan-cytokeratine. In addition, the differentiation of the NMMEE cells was characterized by evaluating the mRNA expression levels of the mucous cell-associated genes Arg2, Muc2, Spdef, Spink4 and Tff1 using quantitative PCR. Notch1, Notch2 and Jagged1 were observed to be co-localized throughout the mouse middle ear epithelium. Furthermore, Notch1-4, Jagged1, Jagged2, Dll1 and Dll4 mRNAs were expressed in the NMMEE cells. The inhibition of Notch by DAPT resulted in fewer EdU-positive cells and the upregulation of the expression levels of various mucous cell-associated genes. The results indicate that DAPT suppresses the proliferation of NMMEE cells while promoting their differentiation into mucous cells. Therefore, DAPT may provide a specific therapeutic strategy for the reversal of multiple pathological processes that are associated with epithelium thickening in the middle ear.

Previous reports have suggested that the level and duration of Atoh1 expression are correlated with the survival, arrangement and stereociliary bundle-related morphology of hair cells during development, but whether Atoh1 expression levels are correlated with the arrangement, bundle formation and electrophysiological characteristics of newly formed hair cells is unknown. To address this question, cultured cochlear explants obtained from neonatal rats were treated with different titers of a human adenovirus serotype 5 (Ad5) vector encoding Atoh1 and/or EGFP (EGFP-Atoh1+/-). The results showed that higher EGFP-Atoh1 concentrations led to higher initial Atoh1 mRNA expression levels and induced greater numbers of ectopic hair cell-like cells (EHCLCs) in the lesser epithelial ridge (LER). Furthermore, gradual increases in the number of EHCLCs were associated with the progressive conversion of the LER region similarly to that of hair cells during development. Some of the cilia on EHCLCs with higher Atoh1 expression were regularly arranged in a manner similar to that of normal hair bundles. As demonstrated through patch clamp recordings, high Atoh1 expression was associated with significantly decreased proportions of cells with Ih currents, significantly reduced proportions of transient potassium channel currents, and potassium channel currents with a greatly increased mean amplitude, which indicated that EHCLCs with high Atoh1 expression were more mature than those with low Atoh1 expression. Overall, the evidence suggests that the Atoh1 expression levels affect not only the arrangement and ciliary morphology of hair cells but also the electrophysiological characteristics of Atoh1-induced EHCLCs, and these findings provide important guidance for future therapies aimed at treating deafness.

Atoh1 overexpression in cochlear epithelium induces new hair cell formation. Use of adenovirus-mediated Atoh1 overexpression has mainly focused on the rat lesser epithelial ridge and induces ectopic hair cell regeneration. The sensory region of rat cochlea is difficult to transfect, thus new hair cells are rarely produced in situ in rat cochlear explants. After culturing rat cochleae in medium containing 10% fetal bovine serum, adenovirus successfully infected the sensory region as the width of the supporting cell area was significantly increased. Adenovirus encoding Atoh1 infected the sensory region and induced hair cell formation in situ. Combined application of the Notch inhibitor DAPT and Atoh1 increased the Atoh1 expression level and decreased hes1 and hes5 levels, further promoting hair cell generation. Our results demonstrate that DAPT enhances Atoh1 activity to promote hair cell regeneration in rat cochlear sensory epithelium in vitro.

Planar cell polarity (PCP) signaling regulates cochlear extension and coordinates orientation of sensory hair cells in the inner ear. Retroviral-mediated introduction of the Math1 transcription factor leads to the transdifferentiation of some mature supporting cells into hair cells. Testosterone, a gonadal sex steroid hormone, is associated with neuroprotection and regeneration in Central Nervous System (CNS) development. Experiments were performed in vitro using Ad5-EGFP-Math1/Ad5-Math1 in neonatal mouse cochleas. Establishment of ectopic hair-cell like cell(HCLC) polarity in the lesser epithelial ridge (LER) with or without testosterone-3-(O-carboxymethyl) oxime bovine serum albumin (testosterone-BSA) treatment was investigated to determine the role of the PCP pathway in regulating ectopic regenerated (HCLCs) through induction by Math1 and testosterone treatment. After Math1 infection, new ectopic regenerated HCLCs were detected in the LER. After the HCLCs developed actin-rich stereocilia, the basal bodies moved from the center to the distal side. Moreover, the narrower, non-sensory LER region meant that the convergent extension (CE) was also established after transfection with Math1. After 9 days of in vitro testosterone-BSA treatment, more Edu(+), Sox2(+), and HCLC cells were observed in the LER with an accompanying downregulation of E-cadherin. Interestingly, the CE of the Ad5-EGFP-math1 treated LER is altered, but the intrinsic cellular polarity of the HCLCs is not obviously changed. In summary, our results indicate that PCP signaling is involved in the development of ectopic HCLCs and the CE of the ectopic sensory region is altered by testosterone-BSA through downregulation of cell–cell adhesion. Testosterone-BSA and Math1 treatment could promote an increase in HCLCs in the LER through proliferation and transdifferentiation.

Sensory hair cells are coordinately oriented within each inner ear sensory organ to exhibit a particular form of planar cell polarity (PCP) necessary for mechanotransduction. However, the developmental events associated with establishing PCP in the vestibule are unclear, hindering data interpretation and employment of the vestibule for PCP studies. Herein, we investigated PCP of the mouse vestibular organs. We further characterised cell cycle exit, cell differentiation, and PCP establishment in the utricle. We found that hair cells formed first in the striolar and medial extrastriolar (MES) regions of the utricle at embryonic day 11.5 (E11.5), while cells in the lateral extrastriolar region (LES) mostly formed at E13.5. Cell differentiation was initiated in the striolar region, which expanded first toward the MES, then to the LES by E15.5. The polarity of hair cells was established at birth along a putative line of polarity reversal (LPR), lateral to the striolar region. Core PCP protein Vangl2 emerged in the cell boundaries since E11.5, while cell intrinsic polarity protein Gαi3 appeared at E12.5, then polarized to the bare zone of individual hair cell at E13.5. These findings provide a blueprint of the developmental events associated with establishing PCP in the utricle.

A new kind of non-Gaussian quantum state is constructed by operating the superposed operator (SO) (cos θaa† + sin θa†a) on a squeezed vacuum state (SVS) S(r)|0〉. It is found that the SOSVS is just a superposition state between S(r)|0〉 and S(r)|2〉 with only even numbers of photons. The nonclassicality is investigated by exploring the negativity of Wigner function (WF) and the sub-Poissonian distribution of Mandel's Q-parameter. The non-Guassianity is exhibited via the fidelity between the SOSVS and the SVS and the marginal distribution of its Wigner function. It is found that such SO on the SVS can enhance the nonclassicality and change the non-Gaussianity of the SOSVS. This provides the possibility of generating quantum states with specific nonclassical and non-Gaussian properties.

Newly formed ectopic hair-cell-like cells (EHCLCs) induced by overexpression of atonal homolog 1 (Atoh1) in vitro were found to possess features of endogenous hair cells (HCs) in previous reports and in the present study. However, limited information is available regarding whether EHCLCs and native spiral ganglion neurons (SGNs) form afferent synapses, which are important for the restoration of hearing. In the current study, we focused on the afferent synaptogenesis between EHCLCs and SGN-derived dendrites. Cochlear explants of auditory epithelia with native SGNs retained were cultured in vitro, and human adenovirus serotype 5 (Ad5) vectors encoding Atoh1 were used to overexpress Atoh1 and induce EHCLCs. We observed that the neurites of the original SGNs extended toward the lesser epithelial ridge (LER) and innervated the EHCLCs. Immunohistochemical analyses revealed the expression of presynaptic ribbon C-terminal-binding protein 2 (CtBP2) and postsynaptic density protein (PSD)-95 in the nerve endings of SGN-derived neurons adjacent to EHCLCs. PSD-95 was located directly opposite CtBP2-positive puncta in the terminals of branches of SGNs, demonstrating that the neurites of SGNs formed afferent-like synaptic connections with EHCLCs. However, the expression of glutamate receptor type 2 (GluR2) could not be detected in the terminals of branches of SGNs surrounding EHCLCs. In addition, we found that the presynaptic ribbon (CtBP2) formation in EHCLCs preceded neural innervation. Furthermore, CtBP2-positive puncta increased and then decreased in EHCLCs, similar to the changes observed in endogenous HCs in terms of their number and distribution. Our finding of the generation of cochlear afferent synapses between EHCLCs and original SGNs will lay the foundation for regenerative approaches to restoring hearing after hair cell loss.

The structural, electronic, and adsorption properties of Li/Na ions on graphene decorated by epoxy groups are investigated by first-principles calculations based on density functional theory. Our results show that the concentration of epoxy groups remarkably affects the structural and electronic properties of graphene. The bandgaps change monotonically from 0.16 eV to 3.35 eV when the O coverage increases from 12.5% to 50% (O/C ratio). Furthermore, the highest lithiation potential of 2.714 V is obtained for the case of graphene oxide (GO) with 37.5 % O coverage, while the highest sodiation potential is 1.503 V for GO with 12.5% O coverage. This clearly demonstrates that the concentration of epoxy groups has different effects on Li and Na storage in GO. Our results provide a new insight into enhancing the Li and Na storage by tuning the concentration of epoxy groups on GO.

Based on EPR’s idea of quantum entanglement, new parameterized coherent-entangled states |α,p〉 μ,ν are introduced in two-mode Fock space, which can be implemented by using a beam splitter. Possible superpositions of |α,p〉 μ,ν result in some new entangled states. The asymmetric ket-bra integration from |α,p〉 μ,ν leads to a new one- and two-mode combinatorial squeezing operator with stronger squeezing, which clearly shows the intrinsic relationship between squeezing mechanism and quantum entanglement.

Atonal homolog 1 (Atoh1) is a basic helix-loop-helix transcription factor that is essential for inner ear hair cell differentiation. Previous studies have reported that Atoh1 gene transfer induces the production of ectopic hair cell-like cells (EHCLCs). In the present study, the effect of different Atoh1 expression levels and the duration of EHCLC formation on the lesser epithelial ridge (LER) of cochleae was examined using a human adenovirus serotype 5 (Ad5) vector encoding atoh1 and the reporter gene EGFP. Different Ad5-EGFP-atoh1/Ad5-EGFP virus titers were added to cultured cochlear explants and EHCLCs were detected in the LER at various time points. The results demonstrated that GFP alone did not induce EHCLCs. By contrast, Atoh1 expression induced EHCLCs as early as 2.5–5 days following EGFP-atoh1 infection in the LER and depending upon the viral titer, the number of EHCLCs increased with time. Higher Ad5-EGFP-atoh1 titers induced enhanced Atoh1 expression, resulting in an increase in EHCLCs. Lower Ad5-EGFP-atoh1 titers required more time for EHCLC formation and very low titers of Ad5-EGFP-atoh1 induced only weak Atoh1 expression and did not trigger EHCLC formation. In conclusion, the present study utilized an appropriate Ad5-EGFP-atoh1 titer range to induce Atoh1 expression and the subsequent production of EHCLCs. The results revealed that the Atoh1 expression level defined the fate of LER cells as either EHCLCs or nonsensory epithelial cells. This evidence may provide an important guideline for future studies into gene therapy strategies for the treatment of deafness.

In this paper, we introduce photon-added and photon-subtracted squeezed vacuum state (PASV and PSSV) and obtain their normalized factors, which have the similar forms involved in Lengendre polynomials. Moreover, we give the compact expressions of Wigner function, which are related to single-variable Hermite polynomials. Especially, we compare their nonclassicality in terms of Mandel Q-factor and the negativity of Wigner function.