Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

Exploring the efficacy of(R)-PFI-2 hydrochloride in mitigating noise-induced hearing loss by targeting NLRP3 inflammasome and NF-κB pathway to reduce inner ear inflammation

Noise-induced hearing loss(NIHL)is primarily driven by inflammatory processes within the cochlea,where noise exposure triggers the activation of the NOD-like receptor protein 3(NLRP3)inflammasome,leading to an inflammatory cascade.The interaction between increased NLRP3 expression and NF-κB activity can further amplify cochlear inflammation.Our findings reveal that(R)-PFI-2 hydrochloride,a selective inhibitor of the SETD7 enzyme,effectively inhibits the activation of the cochlear NF-κB pathway,suppresses the release of proinflammatory factors,and prevents inflammasome assembly.This intervention disrupts the perpetuating cycle of inflammation,thereby alleviating damage to cochlear hair cells attributed to acoustic trauma.Consequently,(R)-PFI-2 hydrochloride emerges as a promising pharmacological candidate for NIHL,targeting and moderating the excessive immune and inflammatory responses implicated in the pathology of hearing loss.

Investigating the expression profiles of cysteine string proteins(CSPs)in cochlear tissue

Objective:This study aims to explore the expression patterns of cysteine string protein alpha(CSPα)and cysteine string protein beta(CSPβ)in the mammalian inner ear,with an emphasis on their temporal dynamics during the developmental stages of C57BL/6 mice.Methods:We utilized immunofluorescence staining to assess the localization and distribution of CSPαand CSPβwithin the inner ears of C57BL/6 mice and miniature pigs.Additionally,this method facilitated the investigation of their temporal expression profiles.Results:In adult C57BL/6 mice and miniature pigs,CSPαand CSPβwere identified in the cytoplasm of inner hair cells and spiral ganglion cells,yet were absent in outer hair cells.Both proteins were found to colocalize with Ctbp2 on the basal side of the cytoplasm in inner hair cells’basilar membrane.Expression of CSPαwas observed at the nerve fiber termini at the basilar membrane’s base of inner and outer hair cells 10 days postnatally in C57BL/6 mice.Notably,expression of both CSPαand CSPβin the cytoplasm of inner hair cells emerged on the 12th day post-birth,aligning with the timeline for registering cochlear potentials.The expression levels of both proteins increased with age,but were consistently absent in outer hair cells.Contrastingly,expression of CSPαand CSPβwas present in the cytoplasm of inner hair cells in miniature pigs as early as one day post-birth,yet remained absent in the three rows of outer hair cells.Conclusion:CSPαand CSPβexhibit predominant and specific expression in inner hair cells and spiral ganglion cells.A unique expression pattern was observed for CSPα,which was also present at the nerve fiber endings of both inner and outer hair cells.The developmental expression trajectory of CSPαand CSPβin mouse inner hair cells is characterized by an initial absence,followed by a gradual increase.Moreover,the timing of expression onset between mice and miniature pigs indicates distinct temporal dynamics,suggesting a potential role in auditory development.

电视新闻报道的视角转换及受众参与空间的形成研究

视角是电视新闻报道中能够选择的新闻事实观审方式,也是记者组织素材进行采访报道的基本路径。在新媒体快速发展的今天,电视新闻报道的视角选择和运用对叙事策略、报道方式以及报道者角色定位至关重要。当下,如何在保持与党的路线方针政策一致的前提下,形成具有吸引力的媒介“看点”和“卖点”,是新闻媒体面临的一大挑战。基于此,文章针对电视新闻报道的视角转换及受众参与空间的形成展开研究,认为媒体无论何时都应坚持马克思主义新闻观,同时关注报道质量和传播效率。文章还指出,在电视新闻报道中,挖掘新闻报道的新“看点”与“卖点”,意味着强调新闻报道的独特性和吸引力,赋予新闻报道更深层次的意义和价值,有助于提高新闻报道的影响力和传播力,使其在激烈的市场竞争中脱颖而出。此外,新闻报道质量与新闻采编人员的专业素养密切相关,而报道视角的选择和运用直接决定新闻能否正确反映现实并有效传达给受众,因而新闻采编人员要提升专业素养,使新闻报道具有故事讲述的“情趣”“理趣”和时代叙事的“韵趣”。

Inflammasome activation in mouse inner ear in response to MCMV induced hearing loss

Objective:To identify presence of inflammasome activated in mouse cochlea with sensorineural hearing loss (SNHL) caused by cytomegalovirus (CMV) infection. Method:MCMV was injected into the right cerebral hemisphere in neonatal BALB/c mice at 2000 pfu virus titers. Auditory brainstem responses (ABRs) were tested to evaluate hearing at 21 days. Histopathological studies were conducted to confirm localizations of MCMV infected cells in the inner ear. Expression of inflammasome related factors was assessed by immunofluorescence, Quantitative real-time PCR and Western blotting. Results:In the mouse model of CMV induced SNHL, inflammasome related kinase Caspase-1 and downstream inflammatory factor IL-1b and IL-18 were found increased and activated after CMV infection in the cochlea. These factors could further up-regulate expression of IL-6 and TNF-a. These inflammatory factors are neurotoxicity and may contribute to hearing impairment. Furthermore, we also detected significantly increased AIM2 protein that accumulated in the SGN of cochleae with CMV infection. Significance:We have shown that inflammasome as a novel inherent immunity mechanism may contribute to hearing impairment. Conclusion:Our data indicate that imflammasome assemble in mouse inner ear in response to CMV infection. We have revealed a novel pa-thology event in CMV induced SNHL involving activation of inflammasome in mouse cochlea. Additionally, we have shown that inflammasome may be a novel target for prevention and treatment of CMV related SNHL. Copyright ? 2016, The Authors. Production & hosting by Elsevier (Singapore) Pte Ltd On behalf of PLA General Hospital Department of OtolaryngologyHead and Neck Surgery. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The mechanism of slope instability due to rainfall-induced structural decay of earthquake-damaged loess

Natural loess slopes are characterized by a strong geological structure,which is an important factor in maintaining slope stability.The magnitude and duration of the earthquake may disturb the soil structure at different levels degrees,locally changing the arrangement between soil particles.The process of rainfall humidification weakens the cementation between soil particles,and the disturbance and humidification change the structural state of the soil,which in turn causes sliding of the slope along with the decay of soil mechanical properties.As slope instability is often the result of a series of post-earthquake ripple effects,it is of great scientific significance to study the mechanism of slope instability due to the structural decay of earthquake-damaged loess exacerbated by rainfall.In this paper,the impact of structural decay of loess on slope stability is simulated by GEOSTUDIO software under three conditions:pre-earthquake rainfall,post-earthquake rainfall and earthquake,taking the landslide in Buzi Village,Min County,Gansu Province as an example.The comparative analysis of the calculation results shows that the structural properties of the slope without earthquake disturbance are influenced by infil-tration amount.When it is fully saturated,the structural properties are similar to those of saturated soil,and the safety factor is reduced by 12.9%.In addition,the earthquake intensity and duration have different degrees of structural damage to the soil.When the structure is fully damaged,it is similar to that of remodelled soil,and the safety factor is reduced by 45.84%.Notably,the process of the earthquake and the following humidification generates the most serious damage to the loess structure,with a reduction in the safety factor of up to 56.15%.The quantitative analysis above obviously illustrates that the post-earthquake rainfall causes the most severe damage to structural loess slopes,and the resulting landslide hazard should not be underestimated.

Hearing analysis in heterozygous and homozygous klotho gene deficient mice

Objective: To understand the crucial role of the klotho gene in hearing development in mouse models.Methods: PCR was used to identify CBA mice with different genotypes, i.e. WT, heterozygous(klotho +/-)or homozygous(klotho-/-). Mice phenotype and weight were recorded postnatal 25 days(P-25) and auditory brainstem responses(ABR) were used to determine auditory function at P-60.Results: klotho-/-mice tended to have smaller size, lighter weight and higher ABR thresholds at P-60,showing early onset age-related hearing loss(ARHL).Conclusion: Heterozygous and homozygous klotho deficient mice exhibit different degrees of hearing loss at young age, with homozygous mice(klotho-/-) showing more severe hearing loss. Our results indicate that persisted expression of klotho protein in the inner ear may potentially delay the onset of ARHL and play an important role in the protection of auditory function.

A screening analysis of the GJB2 c.176 del 16 mutation responsible for hereditary deafness in a Chinese family

Objective:To determine whether a new-born child from a family carrying a deafness gene needs cochlear implantation to avoid dysphonia by screening and sequencing a deafness-related gene.Results:Both screening and sequencing results confirmed that the new born child had a normal GJB2 gene despite the fact that she has a brother suffering from hearing loss triggered by an allelic GJB2 c.176 del 16 mutation.We cloned the GJB2 genes derived from their respective blood genomic DNA into GFP fused plasmids and transfected those plasmids into the 293 T cell line to test for gene function.While the mutated GJB2gene(GJB2 c.176 del 16) of her deaf brother was found to be unable to form the gap junction structure between two adjacent cells,the baby girl’s GJB2 gene ran into no such problems.Conclusion:The screening and sequencing as well as the GJB2 gene function tests invariably showed results consistent with the ABR tested hearing phenotype,which means that the child,with a normal wild type GJB2 gene,does not need early intervention to prevent her from developing hearing loss and dysphonia at a later stage in life.

Global track extraction for probability hypothesis density filter

The probability hypothesis density (PHD), a well-known scheme for multi-target tracking in clutters, can obtain peaks of possible tracks, and its cluster-indexed method is widely accepted in further track extraction. However, the track extraction may face high risk in the case that the targets are so approached that it is hardly to discern their measurements. The concept of the distance between track sets in two adjacent times is defined and a consistency measure metric between any two peaks in two adjacent times is further proposed based on 'global information', containing spatial information (topology feature) among tracks, along with the temporal information of each track. Then, a global track extraction method is proposed based on the consistency belief and four decision rules. Via the simulation comparison with the cluster-indexed method, the proposed method can avoid the track break and mistake association. © 2016 Beijing Institute of Aerospace Information.

Vestibular-evoked myogenic potentials in miniature pigs

Objective:To report detection of vestibular-evoked myogenic potentials (VEMPs) in the miniature pig. Methods:Potentials evoked by 1000 Hz tone bursts were recorded from neck extensor muscles and the masseter muscles in normal adult Bama miniature pigs anesthetized with 3%pentobarbital sodium and Carbachol II. Results:The latency of the first positive wave P from neck extensor muscles was 7.65 ± 0.64 ms, with an amplitude of 1.66 ± 0.34 uv and a rate of successful induction of 75%at 80 dB SPL. The latency of potentials evoked from the masseter muscles was 7.60 ± 0.78 ms, with an amplitude of 1.31 ± 0.28 uv and a rate successful induction of 66%at 80 dB SPL. Conclusion:The latencies and thresholds of VEMPs recorded from the neck extensor muscle and the masseter muscle appear to be comparable in normal adult Bama miniature pigs, although the amplitude recorded from the neck extensor muscle seems to be higher than that from the masseter muscle. However, because of their usually relatively superficial and easily accessible location, as well as their large volume and strong contractions, masseter muscles may be better target muscles for recording myogenic potentials.

Polymorphism of the 86th amino acid in CX26 protein and hereditary deafness

Objective:To investigate the membrane localization function of the CX26 protein when its 86th amino acid is Thr, Ser or Arg, and its relations to deafness. Methods:CX26-GFP protein with either Thr, Ser or Arg as the 86th amino acid was expressed in mouse SGN cells via the GFP fusion type lenti-virus expression system. The membrane localization of the fusion protein was observed under a fluorescence microscope. Results:The mutated protein of CX26 T86S was localized to cell membrane and form gap conjunction structures, showing no difference to the wild type CX26 protein (with Thr as the 86th amino acid). However, the gap conjunction structure disappeared when the mutation was CX26 T86A. Conclusion:These results indicate that the CX26 T86R mutation may be a cause of hearing loss, but CX26 T86S as a non-pathogenic poly-morphism mutation does not affect functions of the CX26 protein. The results are in accordance with the results of clinical screening.

Rigid–flexible hybrid surfaces for water-repelling and abrasionresisting

Droplets impacting solid superhydrophobic surfaces is appealing not only because of scientific interests but also for technological applications such as water-repelling.Recent studies have designed artificial surfaces in a rigid–flexible hybrid mode to combine asymmetric redistribution and structural oscillation water-repelling principles,resolving strict impacting positioning;however,this is limited by weak mechanical durability.Here we propose a rigid–flexible hybrid surface(RFS)design as a matrix of concave flexible trampolines barred by convex rigid stripes.Such a surface exhibits a 20.1%contact time reduction via the structural oscillation of flexible trampolines,and even to break through the theoretical inertial-capillary limit via the asymmetric redistribution induced by rigid stripes.Moreover,the surface is shown to retain the above water-repelling after 1,000 abrasion cycles against oilstones under a normal load as high as 0.2 N·mm−1.This is the first demonstration of RFSs for synchronous waterproof and wearproof,approaching real-world applications of liquid-repelling.

Andrographolide Attenuates Noise-Induced Hearing Loss by Ameliorating Cochlear Inflammation

Objective:This study aimed to explore andrographolide's mechanism of action and its protective effect on noise-induced hearing loss(NIHL).Materials and Methods:A mice animal model for NIHL was established through exposure to broadband noise at 120 d B sound pressure level for 4 h.Transcriptomics analysis and pharmacodynamic experiments were carried out.Results:Andrographolide enters the inner ear and effectively prevents hearing damage following noise exposure in the mice model for permanent hearing loss.Moreover,treatment with andrographolide inhibited the excessive activation of inflammatory factors in the cochleae of noise-exposed mice.Conclusion:Andrographolide might be a promising candidate for auditory protective drug investigation.

Rb Protein is Essential to the Senescence-Associated Heterochromatic Foci Formation Induced by HMGA2 in Primary WI38 Cells

Cellular senescence is an irreversible form of cell cycle arrest that provides a barrier to neoplastic transformation. The integrity of the Rb （Retinoblastoma） pathway is necessary for the formation of the senescence-associated heterochromatin foci （SAHF） that offers a molecular basis for the stability of the senescent state. Surprisingly, although high mobility group A2 protein （HMGA2） can promote tumorigenesis and inhibit Rb function in tumor cells, high-level expression of HMGA2 is sufficient to induce SAHF formation in primary cells. It therefore becomes significant to determine whether Rb protein is necessary in HMGA2-induced SAHF formation. In this study, we established the cellular senescence and SAHF assembly W138 cell model by ectopic expression of HMGA2, in which typical senescent markers were seen, including notable upregulation of p53, p21 and p16, and elevated SA-[3-galactosidase staining together with downregulation of E2F target genes. We then showed that the Rb pathway inhibitor E7 protein was able to partly abolish the ability of SAHF formation alter HMGA2 expression in W138 cells, indicating that Rb is a crucial factor for HMGA2-induced SAHF formation. However. Rb depletion did not completely rescue the cell growth arrest induced by HMGA2, suggesting that Rb is not an exclusive pathway for HMGA2-induced senescence in W138 cells.

LDL receptor-related protein 1 (LRP1),a novel target for opening the blood-labyrinth barrier(BLB)

Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide.However,the presence of the blood-labyrinth barrier(BLB)on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability,which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue.Here,we report the finding of a novel receptor,low-density lipoprotein receptor-related protein 1(LRP1),that is expressed on the BLB,as a potential target for shuttling therapeutics across this barrier.As a proof-ofconcept,we developed an LRP1-binding peptide,IETP2,and covalently conjugated a series of model small-molecule compounds to it,including potential drugs and imaging agents.All compounds were successfully delivered into the inner ear and inner ear lymph,indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB.The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.

GATA2^(−/−) human ESCs undergo attenuatedendothelial to hematopoietic transition andthereafter granulocyte commitment

Background: Hematopoiesis is a progressive process collectively controlled by an elaborate network of transcriptionfactors (TFs). Among these TFs, GATA2 has been implicated to be critical for regulating multiple steps of hematopoiesisin mouse models. However, whether similar function of GATA2 is conserved in human hematopoiesis, especially duringearly embryonic development stage, is largely unknown.Results: To examine the role of GATA2 in human background, we generated homozygous GATA2 knockout humanembryonic stem cells (GATA2^(−/−) hESCs) and analyzed their blood differentiation potential. Our results demonstratedthat GATA2^(−/−) hESCs displayed attenuated generation of CD34^(+)CD43^(+) hematopoietic progenitor cells (HPCs), due tothe impairment of endothelial to hematopoietic transition (EHT). Interestingly, GATA2^(−/−) hESCs retained the potentialto generate erythroblasts and macrophages, but never granulocytes. We further identified that SPI1 downregulationwas partially responsible for the defects of GATA2^(−/−) hESCs in generation of CD34^(+)CD43^(+) HPCs and granulocytes.Furthermore, we found that GATA2^(−/−) hESCs restored the granulocyte potential in the presence of Notch signaling.Conclusion: Our findings revealed the essential roles of GATA2 in EHT and granulocyte development throughregulating SPI1, and uncovered a role of Notch signaling in granulocyte generation during hematopoiesis modeled byhuman ESCs.

Pneumatic programmable superrepellent surfaces

Morphological transformation of surface structures is widely manifested in nature and highly preferred for many applications such as wetting interaction;however,in situ tuning of artificial morphologies independent of smart responsive materials remains elusive.Here,with the aid of microfluidics,we develop a pneumatic programmable superrepellent surface by tailoring conventional wetting materials(e.g.,polydimethylsiloxane)with embedded flexible chambers connecting a microfluidic system,thus realizing a morphological transformation for enhanced liquid repellency based on a nature‐inspired rigid‐flexible hybrid principle(i.e.,triggering symmetry breaking and oscillator coupling mechanisms).The enhancement degree can be in situ tuned within around 300 ms owing to pneumatically controllable chamber morphologies.We also demonstrate that the surface can be freely programmed to achieve elaborated morphological pathways and gradients for preferred droplet manipulation such as directional rolling and bouncing.Our study highlights the potential of an in situ morphological transformation to realize tunable wettability and provides a programmable level of droplet control by intellectualizing conventional wetting materials.

Photonic topological transition in dimerized chains with the joint modulation of near-field and far-field couplings

Topological systems containing near-field or far-field couplings between unit cells have been widely investigated in quantum and classic systems.Their band structures are well explained with theories based on tight-binding or multiple scattering formalism.However,characteristics of the topology of the bulk bands based on the joint modulation of near-field and far-field couplings are rarely studied.Such hybrid systems are hardly realized in real systems and cannot be described by neither tight-binding nor multiple scattering theories.Here,we propose a hybrid-coupling photonic topological insulator based on a quasi-1D dimerized chain with the coexistence of near-field coupling within the unit cell and far-field coupling among all sites.Both theoretical and experimental results show that topological transition is realized by introducing near-field coupling for given far-field coupling conditions.In addition to closing and reopening the bandgap,the change in near-field coupling modulates the effective mass of photonics in the upper band from positive to negative,leading to an indirect bandgap,which cannot be achieved in conventional dimerized chains with either far-field or near-field coupling only.

Spatially-resolved relaxor to ferroelectric phase switching in 0.93Na_(1/2)Bi_(1/2)TiO_(3)-0.07BaTiO_(3) ceramics

In situ,spatially-resolved synchrotron X-ray diffraction was utilized to investigate the electric fieldinduced heterogenous phase transformation of nonergodic relaxor 0.93Na^(1/2)Bi^(1/2)TiO_(3)-0.07BaTiO_(3) ceramics.A Cu electrode was coated on one surface of a rectangular sample by aerosol deposition(AD),while a Pt layer was deposited on the opposite surface by sputter deposition.It is anticipated that a different stress state and/or domain morphology should occur on the AD deposited Cu electrode side due to the particle impact-consolidation deposition process.Under an electric field,different sample regions,i.e.,AD,Middle,and Sputter sides,showed systematic changes in the relaxor to ferroelectric phase transition behavior.In particular,most<001>grains transformed at a sub-coercive field of 0.8 kV/mm,while the majority of the<111>grains only appeared to undergo transitions at a higher field(2.4 kV/mm).Also,the tetragonal phase became the dominant structure at higher field levels.Importantly,both<111>and<001>grains undergo phase switching at lower fields in the region close to the AD-processed layer.The study indicates that the AD process-induced stress can facilitate the electric field-induced relaxor to ferroelectric phase transition,i.e.,the AD Cu side showed more significant lattice strain and domain texture than the sputter Pt side.