Role of macrophage bioenergetics in N-acetylcysteine-mediated mitigation of lung injury and oxidative stress induced by nitrogen mustard.

Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.

Suppression of Lung Oxidative Stress, Inflammation, and Fibrosis following Nitrogen Mustard Exposure by the Selective Farnesoid X Receptor Agonist Obeticholic Acid.

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause pulmonary injury that can progress to fibrosis. NM toxicity is associated with an influx of inflammatory macrophages in the lung. Farnesoid X receptor (FXR) is a nuclear receptor involved in bile acid and lipid homeostasis that has anti-inflammatory activity. In these studies, we analyzed the effects of FXR activation on lung injury, oxidative stress, and fibrosis induced by NM. Male Wistar rats were exposed to phosphate-buffered saline (vehicle control) or NM (0.125 mg/kg) by intratracheal Penncentury-MicroSprayer aerosolization; this was followed by treatment with the FXR synthetic agonist, obeticholic acid (OCA, 15 mg/kg), or vehicle control (0.13-0.18 g peanut butter) 2 hours later and then once per day, 5 days per week thereafter for 28 days. NM caused histopathological changes in the lung, including epithelial thickening, alveolar circularization, and pulmonary edema. Picrosirius red staining and lung hydroxyproline content were increased, indicative of fibrosis; foamy lipid-laden macrophages were also identified in the lung. This was associated with aberrations in pulmonary function, including increases in resistance and hysteresis. Following NM exposure, lung expression of HO-1 and iNOS, and the ratio of nitrates/nitrites in bronchoalveolar lavage fluid (BAL), markers of oxidative stress increased, along with BAL levels of inflammatory proteins, fibrinogen, and sRAGE. Administration of OCA attenuated NM-induced histopathology, oxidative stress, inflammation, and altered lung function. These findings demonstrate that FXR plays a role in limiting NM-induced lung injury and chronic disease, suggesting that activating FXR may represent an effective approach to limiting NM-induced toxicity. SIGNIFICANCE STATEMENT: In this study, the role of farnesoid-X-receptor (FXR) in mustard vesicant-induced pulmonary toxicity was analyzed using nitrogen mustard (NM) as a model. This study's findings that administration of obeticholic acid, an FXR agonist, to rats reduces NM-induced pulmonary injury, oxidative stress, and fibrosis provide novel mechanistic insights into vesicant toxicity, which may be useful in the development of efficacious therapeutics.

Perceptual Pattern of Cleft-Related Speech: A Task-fMRI Study on Typical Mandarin-Speaking Adults.

Congenital cleft lip and palate is one of the common deformities in the craniomaxillofacial region. The current study aimed to explore the perceptual pattern of cleft-related speech produced by Mandarin-speaking patients with repaired cleft palate using the task-based functional magnetic resonance imaging (task-fMRI) technique. Three blocks of speech stimuli, including hypernasal speech, the glottal stop, and typical speech, were played to 30 typical adult listeners with no history of cleft palate speech exploration. Using a randomized block design paradigm, the participants were instructed to assess the intelligibility of the stimuli. Simultaneously, fMRI data were collected. Brain activation was compared among the three types of speech stimuli. Results revealed that greater blood-oxygen-level-dependent (BOLD) responses to the cleft-related glottal stop than to typical speech were localized in the right fusiform gyrus and the left inferior occipital gyrus. The regions responding to the contrast between the glottal stop and cleft-related hypernasal speech were located in the right fusiform gyrus. More significant BOLD responses to hypernasal speech than to the glottal stop were localized in the left orbital part of the inferior frontal gyrus and middle temporal gyrus. More significant BOLD responses to typical speech than to the glottal stop were localized in the left inferior temporal gyrus, left superior temporal gyrus, left medial superior frontal gyrus, and right angular gyrus. Furthermore, there was no significant difference between hypernasal speech and typical speech. In conclusion, the typical listener would initiate different neural processes to perceive cleft-related speech. Our findings lay a foundation for exploring the perceptual pattern of patients with repaired cleft palate.

In vitro investigation on lactic acid bacteria isolatedfrom Yak faeces for potential probiotics.

In order to evaluate the potential and safety of lactic acid bacteria (LAB) isolated from faeces samples of Ganan yak as probiotic for prevention and/or treatment of yak diarrhea, four strains of LAB including Latilactobacillus curvatus (FY1), Weissella cibaria (FY2), Limosilactobacillus mucosae (FY3), and Lactiplantibacillus pentosus (FY4) were isolated and identified in this study. Cell surface characteristics (hydrophobicity and cell aggregation), acid resistance and bile tolerance, compatibility, antibacterial activity and in vitro cell adhesion tests were also carried out to evaluate the probiotic potential of LAB. The results showed that the four isolates had certain acid tolerance, bile salt tolerance, hydrophobicity and cell aggregation, all of which contribute to the survival and colonization of LAB in the gastrointestinal tract. There is no compatibility between the four strains, so they can be combined into a mixed probiotic formula. Antimicrobial tests showed that the four strains were antagonistic to Escherichia coli, Staphylococcus aureus, and Salmonella typhimurium. Moreover, the in vitro safety of the four isolates were determined through hemolytic analysis, gelatinase activity, and antibacterial susceptibility experiments. The results suggest that all the four strains were considered as safe because they had no hemolytic activity, no gelatinase activity and were sensitive to most antibacterial agents. Moreover, the acute oral toxicity test of LAB had no adverse effect on body weight gain, food utilization and organ indices in Kunming mice. In conclusion, the four LAB isolated from yak feces have considerable potential to prevent and/or treat yak bacterial disease-related diarrhea.

Ultrasonic Imaging Investigation of Tongue Movement Patterns of Cleft-Related Lateralized and Palatalized Misarticulation.

OBJECTIVES: To explore the tongue movement patterns on Mandarin speaking children with repaired cleft palate with lateralized and palatalized misarticulation (LPM) using ultrasound imaging technique. METHODS: A group of 20 subjects who were diagnosed with speech sound disorder after cleft palate repairment, and another group of 18 children with LPM were recruited. A group of 20 typical children were recruited as the control group. The ultrasonography was used to collect the articulation pattern of the 8 single vowels that are /a/, /o/, / ɘ/, /i/, /u/, /y/, /ɨ/, /ʉ/ in Mandarin Chinese. Various ultrasonic tongue parameters were analyzed from both sagittal and coronal planes. RESULTS: Compared with the control group, coronal height of peak point, coronal tongue dorsum constraint index, sagittal peak point offset distance, sagittal distance between tongue tip and peak point, and sagittal tongue dorsum constraint index of /ɘ/,/i/, /y/ and /ɨ/ were significantly smaller in the cleft-related lateralized and palatalized group (CLP) and noncleft-related lateralized and palatalized group (NLP) ( P   <  0.05). Compared with the noncleft-related later- alized and palatalized group and control group, sagittal peak point offset distance of the vowels /ɘ/ and /i/ was significant smaller in the cleft-related lateralized and palatalized group group ( P  < 0.05). CONCLUSIONS: The ultrasound images on the children with cleft palate showed a midline elevation of the tongue and a significant apical constriction. The children with LPM showed a midline elevation at the coronal plane and anterior movement of the tongue high point at the sagittal plane. The apical vowels were more informative and accurate in indicating the features of LPM than other vowels.

Voice onset time of alveolar stop /t/ and realization of unaspirated affricates associated with Mandarin-speaking children with repaired cleft palate.

PURPOSE: To examine perceptually the realization of unaspirated affricates and voice onset time (VOT) features of /t/ in Mandarin-speaking children with repaired cleft palate, and to explore the difficulties associated with unaspirated affricate production from the perspective of the VOT of /t/. METHOD: Twenty-three children with repaired cleft palate and 22 age-matched typical native Mandarin speakers were recruited. Speakers with cleft palate were allocated into two groups based on expert perceptual judgment of nasality: one group with perceived normal resonance (PNR) (n = 14, average age = 9.3 years), and another group with perceived hypernasal resonance (PHR) (n = 9, average age = 10.3 years). INTERVENTION: Stimuli were collected through a series of picture naming tasks, targeting the production of initial consonants /t/ and three unaspirated Mandarin affricates /ts, tʂ, tɕ/. The productions of each affricate were evaluated by two experienced speech therapists. The VOT of /t/ was measured using PRAAT speech analysis software. RESULT: The majority of unaspirated affricates were omitted and/or weakly realized by the group of PHR speakers, but not for the PNR group. A significantly smaller mean VOT value associated with /t/ was identified for the PHR group, as compared to the PNR group. A group difference for VOT value was not found between the PNR group and the typical control group. CONCLUSION: The voicing features of /t/ and omitted/weak realization of unaspirated affricates identified in the PHR group indicated that the deviant production of unaspirated affricates in the cleft palate group could be associated with the voicing characteristics of the alveolar stop /t/, and this merits further investigation.

Spectral moment analysis of affricates produced by Mandarin-speaking pre-adolescents with repaired cleft palate.

OBJECTIVE: To explore the spectral differences in frication noise between aspirated and unaspirated affricates in typical Putonghua (standard Mandarin Chinese) pre-adolescent speakers, and to compare the spectral characteristics of affricate production between speakers with repaired cleft palate and their non-cleft peers. PARTICIPANTS AND INTERVENTION: Spectral moment analysis, a quantitative approach to capture the contour of speech spectra, was carried out on speech samples produced by two groups of speakers: (a) speakers with repaired cleft palate (n=14, mean age=11.7 years) and (b) typical speakers (n=10, mean age=11.0 years). RESULTS: Data from typical speakers showed that the unaspirated affricates had significantly higher first spectral moment (M1) than their aspirated counterparts. Compared with typical speakers, individuals with repaired cleft palate exhibited a lower first moment for the four affricates /ts, tʂ, tɕ(h), tɕ/. CONCLUSION: The results revealed important acoustical differences between aspirated and unaspirated affricates for typical speakers. The trend of spectral deviation may have contributed to the difficulty in producing unaspirated affricates found in Putonghua-speaking individuals with speech disorders related to cleft palate.

Consonant accuracy in Mandarin-speaking children with repaired cleft palate.

OBJECTIVE: To compare the consonant production of Chinese-speaking cleft palate children with perceived hypernasal resonance (PHR) after palatoplasty and those with perceived normal resonance (PNR), and to assess the possible influence of language on articulation. SETTING: Two hospital cleft lip and palate centers in mainland China. PARTICIPANTS: Thirty-one speakers were allocated into two groups based on perceptual judgment results of their resonance provided by three speech therapists: one group with PNR (n=20, average age=9.3 years), and another group with PHR (n=11, average age=8.3 years). All participants had no known hearing or cognitive deficits. INTERVENTION: Articulation was evaluated using two Mandarin Chinese assessment tools, the Putonghua Segmental Phonology Test and the Deep Test for Cleft Palate Speakers in Putonghua. Speaker consonant accuracy was evaluated by two experienced speech therapists. RESULTS: Compared to individuals with PNR, the PHR group exhibited more difficulties on production of unaspirated consonants, including/b/,/t/,/k/,/ts/,/tʂ/ and/tɕ/, than for aspirated consonants. CONCLUSION: The distinctive feature of aspiration in Mandarin phonology brought a language specific pattern to consonant production among those speakers with PHR after primary palatal closure.

Spectral features and perceptual judgment of place of affricate in Putonghua-speaking pre-adolescents with normal and cleft palate.

PURPOSE: The aim of the study was to examine the relationship between the spectral features and perceptual judgments of places of affricate in Putonghua (standard Mandarin Chinese), and to explore the possible contribution of different spectral moments on correct perception of place of articulation information by typical pre-adolescent speakers and those with cleft palate. METHOD: A total of 139 affricates produced by 10 normal pre-adolescent speakers and 14 speakers with repaired cleft palate (distorted articulation) were presented to 12 listeners tasked with making a judgment of the accuracy of place of articulation using a visual analog scale. RESULTS: Statistical analysis showed a significant relationship between the third spectral moment (L3) and listeners' perceptual judgment of typical alveolar and retroflex affricates. For productions by pre-adolescents with cleft palate, the first spectral moment (M1) was significantly correlated with listener perceptual scaling of retroflex affricates, but not for the alveolar affricates. CONCLUSION: Spectral features were associated with the perception of place of affricate in Putonghua. Different spectral moment characteristics might be used by listeners when perceiving speech from individuals with cleft palate.

[Applied research on the physical model for calculating optical constant of metal oxide films].

In the present paper, two metal oxide films of HfO2 and Ta2 O5 were prepared by ion beam sputtering technology. Through measuring ellipsometric parameters of HfO2 and Ta2O5 films, their optical constants can be inversion-calculated by nonlinear least squares techniques. In the fitting process, eight experiment groups were arranged by the orthogonal table L8 (2(7)). After selecting Cauchy model, the largest influencing factor for fitting optical constant of HfO2 is surface layer model and the largest influencing factor for fitting optical constant of Ta2 O5 is refractive index gradient model. The impact of different physical model on MSE and the order for selecting model in the fitting process are determined. According to the selecting model and the determined fitting order, optical constants of the two metal oxide films were inversion-calculated with adding weak absorption model, and the obtained MSE can descend 79% and 39% according to the initial value. The results indicated that the selecting model possesses definite physical significance in the fitting process. The obtained method can be applied in inversion-calculating many metal oxide films with weak absorption. It has wide application value. At 500 nm, the refractive index gradient of Ta2O5 films is greater than HfO2 films, while the extinction coefficient of HfO2 films is greater than Ta2O5. It was shown that Hf metal is easier to form stable oxide than Ta metal. And the absorption of HfO2 films is larger than Ta2O5 films.

Optical and interfacial layer properties of SiO2 films deposited on different substrates.

SiO2 films were deposited on fused silica, silicon, glass, germanium, and sapphire substrates by an ion beam sputtering technique. The optical properties of SiO2 films on different substrates and interfacial layer properties between SiO2 films and different substrates were researched by the spectroscopic ellipsometry technique. The refractive indices of SiO2 films deposited on different substrates are about 1.477 at the wavelength of 632.8 nm. The optical anisotropy property of SiO2 films on fused silica substrate is the best. The impact of thermal treatment on surface roughness and interfacial layer properties between SiO2 films and Si substrates were also investigated. When the annealing temperature is 550°C, the least surface thickness and thinnest interface layer thickness between v films and silicon substrate can be achieved. The results indicate that the surface and interface layer properties between SiO2 films and silicon substrate can be greatly improved when the optimum annealing temperature is selected.

Evaluation of speech errors in Putonghua speakers with cleft palate: a critical review of methodology issues.

Speech errors associated with cleft palate are well established for English and several other Indo-European languages. Few articles describing the speech of Putonghua (standard Mandarin Chinese) speakers with cleft palate have been published in English language journals. Although methodological guidelines have been published for the perceptual speech evaluation of individuals with cleft palate, there has been no critical review of methodological issues in studies of Putonghua speakers with cleft palate. A literature search was conducted to identify relevant studies published over the past 30 years in Chinese language journals. Only studies incorporating perceptual analysis of speech were included. Thirty-seven articles which met inclusion criteria were analyzed and coded on a number of methodological variables. Reliability was established by having all variables recoded for all studies. This critical review identified many methodological issues. These design flaws make it difficult to draw reliable conclusions about characteristic speech errors in this group of speakers. Specific recommendations are made to improve the reliability and validity of future studies, as well to facilitate cross-center comparisons.