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Abstract Background Cochlear implants have helped over one million individuals restore functional hearing globally, but their clinical utility in suppressing tinnitus has not been firmly established. Methods In a decade-long study, we examined longitudinal effects of cochlear implants on tinnitus in 323 post-lingually deafened individuals including 211 with pre-existing tinnitus and 112 without tinnitus. The primary endpoints were tinnitus loudness and tinnitus handicap inventory. The secondary endpoints were speech recognition, anxiety and sleep quality. Results Here we show that after 24 month implant usage, the tinnitus cohort experience 58% reduction in tinnitus loudness (on a 0–10 scale from 4.3 baseline to 1.8 = −2.5, 95% CI: −2.7 to −2.2, p = 3 x 10−6; effect size d’ = −1.4,) and 44% in tinnitus handicap inventory (=−21.2, 95% CI: −24.5 to −17.9, p = 1 x 10−15; d’=−1.0). Conversely, only 3.6% of those without pre-existing tinnitus develop it post-implantation. Prior to implantation, the tinnitus cohort have lower speech recognition, higher anxiety and poorer sleep quality than the non-tinnitus cohort, measured by Mandarin monosyllabic words, Zung Self-rating Anxiety Scale and Pittsburgh Sleep Quality Index, respectively. Although the 24 month implant usage eliminate the group difference in speech and anxiety measures, the tinnitus cohort still face significant sleep difficulties likely due to the tinnitus coming back when the device was inactive at night. Conclusions The present result shows that cochlear implantation can offer an alternative effective treatment for tinnitus. The present result also identifies a critical need in developing always-on and atraumatic devices for tinnitus patients, including potentially those with normal hearing.

Long-chain esters (LCEs) are known to affect aroma perception, but the mechanism of their effects remains unclear. In this study, ethyl palmitate (EP), an important LCE in Osmanthus fragrans flower absolute (OFFA), was selected as a target to identify its role and mechanism. The release characteristics of 10 aroma compounds from OFFA with and without EP were obtained by headspace gas chromatography mass spectrometry (HS-GC/MS) and olfactometry evaluation, respectively. The results show that EP changes the release behaviors of volatile compounds in solution, increases their olfactory detection thresholds (ODTs), and reduces the equilibrium headspace concentrations. According to Whitman’s two-film model, EP was found to change the partition coefficients and mass transfer coefficients of the compounds between the liquid and gas phases. This indicates that EP plays an important role in the scent formation of a flavor product and that it is very valuable for the style design of the flavor product.

Background Noise and drug-induced hearing loss (HL) is becoming more and more serious, but the integration and analysis based on transcriptomics and proteomics are lacking. On the one hand, this study aims to integrate existing public transcriptomic data on noise and gentamicin-induced HL. On the other hand, the study aims to establish the gentamicin and noise-induced HL model of guinea pigs, then to perform the transcriptomic and proteomic analyses. Through comprehensive analysis of the above data, we aim to screen, predict, and preliminarily verify biomarkers closely related to HL.

Abstract Objectives To describe the prevalence of self-reported musculoskeletal disorders among workers in the electronics manufacturing industry and to investigate the relations between work-related musculoskeletal disorders (WMSDs) and work-related variables. Methods An interview-based questionnaire survey was carried out in thirty electronics manufacturing factories in China in 2018. The prevalence of WMSDs was estimated using the modified Nordic Musculoskeletal Questionnaire (NMQ). A multivariate logistic regression model was applied to evaluate the effects of risk factors on WMSDs on multiple body parts. Results The 12-month prevalence of WMSDs among participants was 40.6%, and the common body sites affected were the neck (26.8%), shoulder (22.8%), upper back (14.9%), and lower back (14.8%). The results of logistic regression showed that female adults, > 5 job tenure and work-related factors (including awkward posture, lifting or carrying weights, excessive repetition, prolonged sitting, monotonous work and working under conditions of cold or temperature variations) led to a higher risk of WMSDs on most body parts. Upper back, wrist/hand and elbow pain levels were significantly higher for workers with vibration. However, more frequently, physical exercise was a protective factor against WMSDs on most body parts except the upper back, leg and knee. Conclusions The study indicates a high prevalence of musculoskeletal pain among the electronics manufacturing industry in China. Different personal and work factors are related to the occurrence of WMSD on different body parts. Preventive measures should be implemented based on the characteristics of WMSD in the electronic manufacturing industry. Furthermore, the training and intervention guidance of ergonomic hazards in the workplace need to be strengthened by understanding the impact of bad posture, avoiding long-term sitting posture and increasing physical activities.

Abstract Cervical cancer is the most common malignant gynecological tumor. Circular RNA (circRNA) circ_0023404 is reported to be upregulated in cervical cancer cells. This aim is to explore the role and mechanism of circ_0023404 in cervical cancer. circ_0023404, microRNA‐636 (miR‐636), and cytochrome P450 2S1 (CYP2S1) levels were detected by real‐time quantitative polymerase chain reaction (RT‐qPCR). Cell proliferation, migration, invasion, and apoptosis were detected by 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) assay, 5‐ethynyl‐2′‐deoxyuridine (EDU) assay, colony formation assay, transwell assay, and cytometry assay. Protein levels of cyclin D1, matrix metallopeptidase 9 (MMP9), Bcl‐2‐associated X protein (Bax), and CYP2S1 were examined by western blot assay. The binding relationship between miR‐636 and circ_0023404 or CYP2S1 was predicted by Circinteractome or targetscan, and then verified by a dual‐luciferase reporter assay and RNA pull‐down assay. circ_0023404 and CYP2S1 expression were increased, and miR‐636 was decreased in cervical cancer tissues and cells. Moreover, circ_0023404 knockdown could repress proliferation, migration, invasion, and promote apoptosis of cervical cancer cells in vitro. Mechanically, circ_0023404 could regulate CYP2S1 expression by sponging miR‐636. circ_0023404 silencing could attenuate the progression of cervical cancer cells partly by targeting the miR‐636/CYP2S1 axis, hinting at a promising therapeutic target for cervical cancer.

The inflammasome is a multiprotein oligomer in the cell cytoplasm and is part of the innate immune system. It plays a crucial role in the pathological process of noise-induced hearing loss (NIHL). However, the mechanisms of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in NIHL have not been clearly demonstrated. In this study, miniature pigs were exposed to white noise at 120 dB(A) and auditory brainstem response measurements were used to measure their hearing function. Immunofluorescence staining, confocal laser scanning microscopy, western blot assay, and quantitative reverse transcription-polymerase chain reaction were used to analyze inflammasome-related protein distribution and expression. NLRP3, interleukin-1β, interleukin-18, and cleaved-caspase-1 were highly expressed in the cochlea after 120 dB(A) white noise exposure. Our findings suggest that NLRP3-inflammasomes in the cochlea may be activated after acoustic trauma, which may be an important mechanism of noise-induced hearing loss.

The objective of this study was using a statistical model to optimize the medium formula and liquid culturing conditions, which was employed to evaluate the potency of pine needles extract as nutritional component in basal medium for culturing Helvella lacunose in order to enhancing the production of mycelia and extracellular polysaccharides (EPS). The most proper carbon and nitrogen source, various fermentation parameters (i.e., initial pH in medium, fermentation time, and temperature) were investigated by single factor test. Based on the experimentation, the optimal concentrations of carbon and nitrogen sources were analyzed by response surface methodology (RSM). The results showed that the optimal medium formula and liquid culturing conditions were 1000 mL pine needles extract, 33.56 g glucose, 4.11 g peptone, 4.06 g YE, 1 g KH2PO4, 1 g NaHCO3, 0.5 g MgSO4, 0.01 g vitamin B1 for the accumulation of mycelial biomass (at pH 6.0, 25°C culturing of 7 days), and EPS (at pH 7.0, 25°C culturing of 10 days). Under optimized medium, the experimental production of mycelia and EPS were 11.78 g/L and 223.16 mg/L, which were 10.52 and 4.85 times than that of control (1.12 ± 0.52 g/L and 46.08 ± 1.18 mg/L, respectively). This data implied that statistical model is very useful tools for optimizing media components and fermentation parameters, and the screened media components and parameters have reference value for further large-scale production.

Abstract Background The SCN11A gene, encoded Nav1.9 TTX resistant sodium channels, is a main effector in peripheral inflammation related pain in nociceptive neurons. The role of SCN11A gene in the auditory system has not been well characterized. We therefore examined the expression of SCN11A in the murine cochlea, the morphological and physiological features of Nav1.9 knockout (KO) ICR mice. Results Nav1.9 expression was found in the primary afferent endings beneath the inner hair cells (IHCs). The relative quantitative expression of Nav1.9 mRNA in modiolus of wild-type (WT) mice remains unchanged from P0 to P60. The number of presynaptic CtBP2 puncta in Nav1.9 KO mice was significantly lower than WT. In addition, the number of SGNs in Nav1.9 KO mice was also less than WT in the basal turn, but not in the apical and middle turns. There was no lesion in the somas and stereocilia of hair cells in Nav1.9 KO mice. Furthermore, Nav1.9 KO mice showed higher and progressive elevated ABR threshold at 16 kHz, and a significant increase in CAP thresholds. Conclusions These data suggest a role of Nav1.9 in regulating the function of ribbon synapses and the auditory nerves. The impairment induced by Nav1.9 gene deletion mimics the characters of cochlear synaptopathy.

Noised-induced hearing loss (NIHL) is an acquired, progressive neurological damage caused by exposure to intense noise in various environments including industrial, military and entertaining settings. The prevalence of NIHL is much higher than other occupational injuries in industrialized countries. Recent studies have revealed that genetic factors, together with environmental conditions, also contribute to NIHL. A group of genes which are linked to the susceptibility of NIHL had been uncovered, involving the progression of oxidative stress, potassium ion cycling, cilia structure, heat shock protein 70 (HSP70), DNA damage repair, apoptosis, and some other genes. In this review, we briefly summarized the studies primary in population and some animal researches concerning the susceptible genes of NIHL, intending to give insights into the further exploration of NIHL prevention and individual treatment.

Abstract Background Knee osteoarthritis (KOA) seriously reduces quality of life and is a major threat to the health of the middle-aged and elderly. This study aimed to assess the efficacy of Miao crossbow needle therapy vs. acupuncture for KOA therapy. Methods This multicenter, randomized controlled trial was performed at three hospitals between April 2016 and December 2016. The patients were randomized to receive crossbow needle (CN) or acupuncture (AT). All treatments were completed within 46 days. Evaluation of treatment was conducted on the 46th, 62nd, and 77th days. The primary endpoint was change of Western Ontario and McMaster Osteoarthritis Index (WOMAC) score on the 46th day. The secondary endpoints included WOMAC score, the Lysholm knee score, the Japanese Orthopedic Association (JOA) knee score, visual analog scale (VAS), and the MOS 36-item short-form health survey (SF-36), on the 46th, 62nd, and 77th day. Results Finally, data of 301 participants were analyzed for the efficacy of treatment. Compared with AT, there was a larger change of WOMAC score in the CN group after treatment [− 25.0 (95% CI − 27.0, − 23.0) vs. − 18.8 (95% CI − 20.8, − 16.9), P

Cytokine secretion, such as interleukin-4 (IL-4), IL-5, IL-9, IL-13, and amphiregulin (Areg), by type 2 innate lymphoid cells (ILC2s) is indispensable for homeostasis, remodeling/repairing tissue structure, inflammation, and tumor immunity. Often viewed as the innate cell surrogate of T helper type 2 (Th2) cells, ILC2s not only secrete the same type 2 cytokines, but are also inextricably related to CD4+T cells in terms of cell origin and regulatory factors, bridging between innate and adaptive immunity. ILC2s interact with CD4+T cells to play a leading role in a variety of diseases through secretory factors. Here, we review the latest progress on ILC2s and CD4+T cells in the lung, the close relationship between the two, and their relevance in the lung disease and immunity. This literature review aids future research in pulmonary type 2 immune diseases and guides innovative treatment approaches for these diseases.

Abstract Background Increasing number of hospitalized children with community acquired pneumonia (CAP) is co-detected with Mycoplasma pneumoniae (Mp). The clinical characteristics and impact of Mp co-detected with other bacterial and/or viral pathogens remain poorly understood. The purpose of this study was to evaluate the demographic and clinical features of CAP children with Mp mono-detection and Mp co-detection. Methods A total of 4148 hospitalized children with CAP were recruited from January to December 2017 at the Children’s Hospital of Hebei Province, affiliated to Hebei Medical University. A variety of respiratory viruses, bacteria and Mp were detected using multiple modalities. The demographic and clinical features of CAP children with Mp mono-detection and Mp co-detection were recorded and analyzed. Results Among the 110 CAP children with Mp positive, 42 (38.18%) of them were co-detected with at least one other pathogen. Co-detection was more common among children aged ≤3 years. No significant differences were found in most clinical symptoms, complications, underlying conditions and disease severity parameters among various etiological groups, with the following exceptions. First, prolonged duration of fever, lack of appetite and runny nose were more prevalent among CAP children with Mp-virus co-detection. Second, Mp-virus (excluding HRV) co-detected patients were more likely to present with prolonged duration of fever. Third, patients co-detected with Mp-bacteria were more likely to have abnormal blood gases. Additionally, CAP children with Mp-HRV co-detection were significantly more likely to report severe runny nose compared to those with Mp mono-detection. Conclusion Mp co-detection with viral and/or bacterial pathogens is common in clinical practice. However, there are no apparent differences between Mp mono-detection and Mp co-detections in terms of clinical features and disease severity.

ObjectiveTo describe and study the population statistics, hearing phenotype, and pathological changes of a porcine congenital single-sided deafness (CSSD) pedigree.MethodsClick auditory brainstem response (ABR), full-frequency ABR, and distortion product otoacoustic emission (DPOAE) were used to assess the hearing phenotype of the strain. Tympanogram was used to assess the middle ear function since birth. Celloidin embedding–hematoxylin–eosin (CE-HE) stain and scanning electron microscopy (SEM) were used to study the pathological changes of cochlear microstructures. Chi-square analysis was used to analyze the relation between hearing loss and other phenotypes.ResultsThe mating mood of CSSD with CSSD was most efficient in breeding-targeted CSSD phenotype (47.62%), and the prevalence of CSSD reached 46.67% till the fifth generation, where 42.22% were bilateral hearing loss (BHL) and 9.00% were normal hearing (NH) individuals. Hearing loss was proved to have no relation with coat color (P = 0.0841 > 0.05) and gender (P = 0.4621 > 0.05) by chi-square analysis. The deaf side of CSSD offspring in the fifth generation had no relation with that of their maternal parent (P = 0.2387 > 0.05). All individuals in this strain exhibited congenital severe to profound sensorineural hearing loss with no malformation and dysfunction of the middle ear. The good hearing ear of CSSD stayed stable over age. The deaf side of CSSD and BHL presented cochlear and saccular degeneration, and the hair cell exhibited malformation since birth and degenerated from the apex to base turn through time. The pathology in BHL cochlea progressed more rapidly than CSSD and till P30, the hair cell had been totally gone. The stria vascularis (SV) was normal since birth and degenerated through time and finally exhibited disorganization of three layers of cells.ConclusionThis inbred porcine strain exhibited high and stable prevalence of CSSD, which highly resembled human non-syndromic CSSD disease. This porcine model could be used to further explore the etiology of CSSD and serve as an ideal tool for the studies of the effects of single-sided hearing deprivation on neural, cognitive, and behavioral developments and the benefits brought by CI in CSSD individuals.

Abstract Background Waardenburg syndrome (WS) is the consequence of an inherited autosomal dominant mutation which causes the early degeneration of intermediate cells of cochlear stria vascularis (SV) and profound hearing loss. Patients with WS may also experience primary vestibular symptoms. Most of the current WS studies did not discuss the relationship between WS and abnormal vestibular function. Our study found that a spontaneous mutant pig showed profound hearing loss and depigmentation. MITF-M, a common gene mutation causes type WS which affect the development of the intermediate cell of SV, was then identified for animal modeling. Results In this study, the degeneration of vestibular hair cells was found in pigs with MITF-M. The morphology of hair cells in vestibular organs of pigs was examined using electron microscopy from embryonic day E70 to postnatal two weeks. Significant hair cell loss in the mutant saccule was found in this study through E95 to P14. Conversely, there was no hair cell loss in either utricle or semi-circular canals. Conclusions Our study suggested that MITF-M gene mutation only affects hair cells of the saccule, but has no effect on other vestibular organs. The study also indicated that the survival of cochlear and saccular hair cells was dependent on the potassium release from the cochlear SV, but hair cells of the utricle and semi-circular canals were independent on SV.

Abstract Background Auditory function and cochlear morphology have previously been described in a porcine model with spontaneous WS2-like phenotype. In the present study, cochlear histopathology was further investigated in the inner ear of the developing spontaneous deafness pig. Results We found that the stria vascularis transformed into a complex tri-laminar tissue at embryonic 85 days (E85) in normal pigs, but not in the MITF−/− pigs. As the neural crest (NC) of cochlea was derived by melanocytes. MITF mutation caused failure of development of melanocytes which caused a subsequent collapse of cochlear duct and deficits of the epithelium after E100. Furthermore, the spiral ganglion neurons of cochlea in the MITF−/− pigs began to degenerate at postnatal 30 days (P30). Thus, our histopathological results indicated that the malformation of the stria vascularis was a primary defect in MITF−/− induced WT pigs which was resulted from the loss of NC-derived melanocytes. Subsequently, the cochleae underwent secondary degeneration of the vestibular organs. As the degeneration of spiral ganglion neurons happened after P30, it suggests that WS patients should be considered as candidates for cochlear implant. Conclusions Our porcine model of MITF-M mutation may provide a crucial animal model for cochlear implant, cell therapy in patients with congenital hereditary hearing loss.

The objective of this study was to explore the molecular mechanisms of acute noise-induced hearing loss and recovery of steady-state noise-induced hearing loss using miniature pigs. We used miniature pigs exposed to white noise at 120 dB (A) as a model. Auditory brainstem response (ABR) measurements were made before noise exposure, 1 day and 7 days after noise exposure. Proteomic Isobaric Tags for Relative and Absolute Quantification (iTRAQ) was used to observe changes in proteins of the miniature pig inner ear following noise exposure. Western blot and immunofluorescence were performed for further quantitative and qualitative analysis of proteomic changes. The average ABR-click threshold of miniature pigs before noise exposure, 1 day and 7 days after noise exposure, were 39.4 dB SPL, 67.1 dB SPL, and 50.8 dB SPL, respectively. In total, 2,158 proteins were identified using iTRAQ. Both gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) database analyses showed that immune and metabolic pathways were prominently involved during the impairment stage of acute hearing loss. During the recovery stage of acute hearing loss, most differentially expressed proteins were related to cholesterol metabolism. Western blot and immunofluorescence showed accumulation of reactive oxygen species and nuclear translocation of NF-κB (p65) in the hair cells of miniature pig inner ears during the acute hearing loss stage after noise exposure. Nuclear translocation of NF-κB (p65) may be associated with overexpression of downstream inflammatory factors. Apolipoprotein (Apo) A1 and Apo E were significantly upregulated during the recovery stage of hearing loss and may be related to activation of cholesterol metabolic pathways. This is the first study to use proteomics analysis to analyze the molecular mechanisms of acute noise-induced hearing loss and its recovery in a large animal model (miniature pigs). Our results showed that activation of metabolic, inflammatory, and innate immunity pathways may be involved in acute noise-induced hearing loss, while cholesterol metabolic pathways may play an important role in recovery of hearing ability following noise-induced hearing loss.

SRY-box 10 (SOX10) mutation may lead to inner ear deformities. However, its molecular mechanisms on inner ear development are not clear. In this work, the inner ear morphology was investigated at different embryonic stages of the SOX10 mutation miniature porcine model with sensorineural hearing loss, and high-throughput RNA-seq and bioinformatics analyses were applied. Our results indicated that the SOX10 mutation in the miniature pigs led to an incomplete partition (IP) of the cochlea, a cystic apex caused by fusion from middle and apical turns, cochlear modiolar defects and a shortened cochlear duct. The model demonstrated 173 differentially expressed genes (DEGs) and 185 differentially expressed long non-coding RNAs (lncRNAs). The down-regulated DEGs most significantly enriched the inflammatory mediator regulation of the TRP channels, arachidonic acid metabolism, and the salivary secretion pathways, while the up-regulated DEGs most significantly enriched the systemic lupus erythematosus and alcoholism pathways. Based on gene cluster analysis, we selected four gene groups: WNT1, KCNQ4, STRC and PAX6.

Ototoxic drugs can be used to produce a loss of cochlear hair cells to create animal models of deafness. However, to the best of our knowledge, there is no report on the establishment of a rat deafness model through the combined application of aminoglycosides and loop diuretics. The aim of this study was to use single or combined administration of furosemide and kanamycin sulfate to establish rat models of deafness. The rats received intravenous injections of different doses of furosemide and/or intramuscular injections of kanamycin sulfate. The auditory brainstem response was measured to determine the hearing threshold after drug application. Immunocytochemistry and confocal microscopy were performed to evaluate inner ear morphology. In the group receiving combined administration of furosemide and kanamycin, the auditory brainstem response threshold showed significant elevation 3 days after administration, higher than that produced by furosemide or kanamycin alone. The hair cells showed varying degrees of injury, from the apical turn to the basal turn of the cochlea and from the outer hair cells to the inner hair cells. The spiral ganglion cells maintained a normal morphology during the first week after the hair cells completely disappeared, and then gradually degenerated. After 2 months, the majority of spiral ganglion cells disappeared, but a few remained. These findings demonstrate that the combined administration of furosemide and kanamycin has a synergistic ototoxic effect, and that these drugs can produce hair cell loss and hearing loss in rats. These findings suggest that even in patients with severe deafness, electronic cochlear implants may partially restore hearing.

14-3-3 proteins belong to a family of phosphoserine/threonine-binding modules and participate in a wide array of signal transduction and regulatory events. Our previous study demonstrated that Ta14-3-3 was significantly down-regulated in leaf and root tissues of hybrid wheat at the tillering stage. In this paper, three homoeologous Ta14-3-3 genes were cloned from common wheat (Triticum aestivum L., 2n=6x=42, AABBDD) and mapped on chromosomes 2A, 2B, and 2D, respectively. Transgenic Arabidopsis plants ectopically overexpressing Ta14-3-3 displayed shorter primary roots, delayed flowering and retarded growth rates, indicating that Ta14-3-3 acted as a growth inhibitor in Arabidopsis. In wheat, Ta14-3-3 was down-regulated in roots and leaves of hybrids as compared to their parental lines. We proposed that Ta14-3-3 proteins might regulate growth vigor in hybrid wheat.

To enlarge the green wave bandwidth between intersections of an artery and to design an effective green wave bandwidth, the conception of partitioned artery was proposed in this article. First, the artery was divided into sections systematically. After the calculation of the average volumes and intervals of the sections, two-way green wave optimization model of arteries based on division of artery was developed. Then, set constraint condition of public cycle by analyzing the relationship between cycle and delay, and the process of searching the bandwidth of partitioned green wave was proposed. Next, the bandwidth of partitioned green wave was optimized by the genetic algorithms with offset and public cycle as variables. Finally, simulation result shows the feasibility and effectiveness of proposed method based on the comparison and analysis of real data in Beijing.

With the rapid development of urban transport and the sharp increase in vehicle population, traffic accidents form one of the most important causes of urban traffic congestion other than the imbalance between traffic supply and demand. Traffic congestion causes severe problems, such as environment contamination and energy dissipation. Therefore, it would be useful to analyze the congestion propagation characteristics after traffic accidents. Numerical analysis and computer simulation were two of the typical methods used at present to study the traffic congestion propagation properties. The latter was more widespread as it is more consistent with the actual traffic flow and more visual than the former. In this paper, an improved cellular automata (CA) model was presented to analyze traffic congestion propagation properties and to evaluate control strategies. In order to apply them to urban traffic flow simulation, the CA models have been improved and expanded on. Computer simulations were built for congestion not only extending to the upstream intersection, but also the upstream intersection and the entire road network, respectively. Congestion propagation characteristics after road traffic accidents were obtained, and controls of different severities and durations were analyzed. The results provide the theoretical foundation and practical means for the control of congestion.

The [ 2 ¯ 33 ] coplanar double-slip-oriented Cu single crystals were pre-fatigued up to a saturation stage and then uniaxially tensioned or compressed to fracture. The results show that for the specimen pre-fatigued at a plastic strain amplitude γpl of 9.2 × 10−4, which is located within the quasi-plateau of the cyclic stress-strain (CSS) curve, its tensile strength and elongation are coincidently improved, showing an obvious strengthening effect by low-cycle fatigue (LCF) training. However, for the crystal specimens pre-fatigued at a γpl lower or higher than the quasi-plateau region, due to a low pre-cyclic hardening or the pre-induction of fatigue damage, no marked strengthening effect by LCF training occurs, and even a weakening effect by LCF damage takes place instead. In contrast, the effect of pre-fatigue deformation on the uniaxial compressive behavior is not so significant, since the compressive deformation is in a stress state more beneficial to the ongoing plastic deformation and it is insensitive to the damage induced by pre-cycling. Based on the observations and comparisons of deformation features and dislocation structures in the uniaxially deformed [ 2 ¯ 33 ] crystal specimens which have been pre-fatigued at different γpl, the micro-mechanisms for the effect of pre-fatigue on the static mechanical behavior are discussed.

The hallmark of mechanosensory hair cells is the stereocilia, where mechanical stimuli are converted into electrical signals. These delicate stereocilia are susceptible to acoustic trauma and ototoxic drugs. While hair cells in lower vertebrates and the mammalian vestibular system can spontaneously regenerate lost stereocilia, mammalian cochlear hair cells no longer retain this capability. We explored the possibility of regenerating stereocilia in the noise-deafened guinea pig cochlea by cochlear inoculation of a viral vector carrying Atoh1, a gene critical for hair cell differentiation. Exposure to simulated gunfire resulted in a 60-70 dB hearing loss and extensive damage and loss of stereocilia bundles of both inner and outer hair cells along the entire cochlear length. However, most injured hair cells remained in the organ of Corti for up to 10 days after the trauma. A viral vector carrying an EGFP-labeled Atoh1 gene was inoculated into the cochlea through the round window on the seventh day after noise exposure. Auditory brainstem response measured one month after inoculation showed that hearing thresholds were substantially improved. Scanning electron microscopy revealed that the damaged/lost stereocilia bundles were repaired or regenerated after Atoh1 treatment, suggesting that Atoh1 was able to induce repair/regeneration of the damaged or lost stereocilia. Therefore, our studies revealed a new role of Atoh1 as a gene critical for promoting repair/regeneration of stereocilia and maintaining injured hair cells in the adult mammal cochlea. Atoh1-based gene therapy, therefore, has the potential to treat noise-induced hearing loss if the treatment is carried out before hair cells die.

Plenty of experiments and data analysis of vehicle track type in road curved section show that the deviation and the crossing characteristics of vehicle track paths are directly related to the driving stability and security. In this paper, the concept of driving dangerous area in curved section was proposed based on the vehicle track characteristics according to driving behavior decision making and accident probability. Taking the observation data of passenger cars as the representative, the vehicle track paths deviation regularity per measurement direction were analyzed by SPSS under the condition of different radius and different road cross section. The distribution probability of different track type and the accident probability calculation methods and results between opposite direction vehicles were given based on the track characteristics. Keywords: Vehicle Track Type; Track Deviation; SPSS Analysis, Accident probability; Driving Decision Making, Driving Dangerous Area.

BACKGROUND: In mammals, hair cells do not undergo spontaneous regeneration when they are damaged and result in permanent hearing loss. Previous studies in cultured Organ of Corti dissected from neonatal animals have shown that both DAPT (r-secretase inhibitor in the Notch signal pathway) treatment and Atoh1 overexpression can induce supernumerary hair cells. The effects of simultaneous DAPT treatment and Atoh1 over expression in the cells of cultured Organ of Corti from neonatal rats are still obscure. PRINCIPAL FINDINGS: In this study, we set out to investigate the interaction of DAPT treatment and Atoh1 overexpression as well as culture time and the location of basilar fragment isolated form neonatal rat inner ear. Our results showed that DAPT treatment induced more hair cells in the apical turn, while Atoh1 overexpression induced more extra hair cells in the middle turn of the cultured Organ of Corti. When used together, their effects are additive but not synergistic. In addition, the induction of supernumerary hair cells by both DAPT and Atoh1 overexpression is dependent on the treatment time and the location of the cochlear tissue. Moreover, DAPT treatment causes dramatic changes in the orientation of the stereociliary bundles of hair cells, whereas Atoh1 overexpression didn't induce drastic change of the polarity of stereociliary bundles. CONCLUSIONS/SIGNIFICANCE: Taken together, these results suggest that DAPT treatment are much more potent in inducing supernumerary hair cells than Atoh1 overexpression and that the new hair cells mainly come from the trans-differentiation of supporting cells around hair cells. The orientation change of stereociliary bundle of hair cells may be attributed to the insertion of the newly formed hair cells. The immature hair bundles on the newly formed hair cells may also contribute to the overall chaos of the stereociliary bundle of the sensory epithelia.

Hereditary hearing loss (HHL), a genetic disorder that impairs auditory function, significantly affects quality of life and incurs substantial economic losses for society. To investigate the underlying causes of HHL and evaluate therapeutic outcomes, appropriate animal models are necessary. Pigs have been extensively used as valuable large animal models in biomedical research. In this review, we highlight the advantages of pig models in terms of ear anatomy, inner ear morphology, and electrophysiological characteristics, as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss. Additionally, we discuss the prospects, challenges, and recommendations regarding the use pig models in HHL research. Overall, this review provides insights and perspectives for future studies on HHL using porcine models. [ABSTRACT FROM AUTHOR]

Herein we have used combined static electronic structure calculations and "on-the-fly" global-switching trajectory surface-hopping dynamics simulations to explore the photochemical mechanism of oxybenzone sunscreen. We have first employed the multi-configurational CASSCF method to optimize minima, conical intersections, and minimum-energy reaction paths related to excited-state intramolecular proton transfer (ESIPT) and excited-state decays in the ¹ππ*, ¹nπ*, and S0 states (energies are refined at the higher MS-CASPT2 level). According to the mapped potential energy profiles, we have identified two ultrafast excited-state deactivation pathways for the initially populated ¹ππ* system. The first is the diabatic ESIPT process along the ¹ππ* potential energy profile. The generated ¹ππ* keto species then decays to the S0 state via the keto ¹ππ*/gs conical intersection. The second is internal conversion to the dark ¹nπ* state near the ¹ππ* /¹nπ* crossing point in the course of the diabatic ¹ππ* ESIPT process. Our following dynamics simulations have shown that the ESIPT and ¹ππ* → S0 internal conversion times are 104 and 286 fs, respectively. Finally, our present work demonstrates that in addition to the ESIPT process and the ¹ππ* → S0 internal conversion in the keto region, the ¹ππ* → ¹nπ* internal conversion in the enol region plays as well an important role for the excited-state relaxation dynamics of oxybenzone. [ABSTRACT FROM AUTHOR]

Background: Clinical trials of cell-based therapies using induced pluripotent stem (iPS) cells have already been started for several neurological diseases. Objective: The purpose of the present study was to explore the characteristics and differentiation of somatic cells in vitro undergoing a low pH treatment, so as to provide new therapeutic strategies for treating sensorineural hearing loss. Methods: Somatic cells were treated with low pH solution to alter their characteristics. In addition, a mouse model of the cochlear lesion was constructed using bilirubin. Subsequently, the characteristics and therapeutic effect of somatic cells undergoing low pH treatment were examined by morphology, alkaline phosphatase (AKP) activity, immunofluorescence assay and q-PCR. Results: The cells in the experimental group grew better than those in the control group. The AKP activity in the experimental group was higher than that in the control group. The expression of Nanog and Oct4 was both positive in the two groups. When the cells were changed to neurobasal medium, the marker of nestin was positive. Conclusion: The human somatic cells undergoing a low pH treatment showed the similar characteristics as those of iPS cells, although the functions and therapeutic effect of these altered human somatic cells need to be further studied. [ABSTRACT FROM AUTHOR]

SRY-box 10 (SOX10) mutation may lead to inner ear deformities. However, its molecular mechanisms on inner ear development are not clear. In this work, the inner ear morphology was investigated at different embryonic stages of the SOX10 mutation miniature porcine model with sensorineural hearing loss, and high-throughput RNA-seq and bioinformatics analyses were applied. Our results indicated that the SOX10 mutation in the miniature pigs led to an incomplete partition (IP) of the cochlea, a cystic apex caused by fusion from middle and apical turns, cochlear modiolar defects and a shortened cochlear duct. The model demonstrated 173 differentially expressed genes (DEGs) and 185 differentially expressed long non-coding RNAs (lncRNAs). The down-regulated DEGs most significantly enriched the inflammatory mediator regulation of the TRP channels, arachidonic acid metabolism, and the salivary secretion pathways, while the up-regulated DEGs most significantly enriched the systemic lupus erythematosus and alcoholism pathways. Based on gene cluster analysis, we selected four gene groups: WNT1, KCNQ4, STRC and PAX6. [ABSTRACT FROM AUTHOR]

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Background: Alkaloids from Piper longum (PLA), extracted from P. longum, have potent anti-inflammatory effects. The aim of this study was to investigate whether PLA could protect dopaminergic neurons against inflammation-mediated damage by inhibiting microglial activation using a lipopolysaccharide (LPS)-induced dopaminergic neuronal damage rat model. Methods: The animal behaviors of rotational behavior, rotarod test and open-field test were investigated. The survival ratio of dopaminergic neurons and microglial activation were examined. The dopamine (DA) and its metabolite were detected by high performance liquid chromatography (HPLC). The effects of PLA on the expression of interleukin (IL)-6, interleukin (IL)-1 β and tumor necrosis factor (TNF)-α were detected by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and nitric oxide (NO) were also estimated. Results: We showed that the survival ratio of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNpc) and DA content in the striatum were reduced after a single intranigral dose of LPS (10 µg) treatment. The survival rate of TH-ir neurons in the SNpc and DA levels in the striatum were significantly improved after treatment with PLA for 6 weeks. The over-activated microglial cells were suppressed by PLA treatment. We also observed that the levels of inflammatory cytokines, including TNF-α, IL-6 and I L- 1 β were decreased and the excessive production of ROS and NO were abolished after PLA treatment. Therefore, the behavioral dysfunctions induced by LPS were improved after PLA treatment. Conclusion: This study suggests that PLA plays a significant role in protecting dopaminergic neurons against inflammatory reaction induced damage. [ABSTRACT FROM AUTHOR]

The influence of on-line bus stop and bus bay on the capacity of roadway links is studied. The vehicle operating characteristics are analyzed by means of bus influence area for each type of bus stop. Based on this calculation model, the capacity of roadway links is developed using queuing theory and gap acceptance theory. And the validity of the model is verified by VISSIM simulation, the average relative errors are 2. 73% and 3. 10% respectively. It shows that this model can accurately calculate the capacity of links affected by bus stops. Finally, the adjustment factors of bus stop are achieved by the model, and some factors, especially dwell time, are analyzed. [ABSTRACT FROM AUTHOR]

A new high-order OTA-C active filter using operational transconductance amplifiers (OTAs) and capacitors is presented. The filter has low sensitivity performance and high cut-off frequencies. Its cut-off frequencies can be controlled by a DC voltage or current. In addition, this filter is suitable for integration. Experimental results are given to show its feasibility. [ABSTRACT FROM AUTHOR]