Involvement of Bmal1 and circadian clock signaling in chondrogenic differentiation of ATDC5 cells by fluoride.

Skeletal fluorosis causes growth plate impairment and growth retardation during bone development. However, the mechanism of how fluoride impairs chondrocyte is unclear. To explore the effect of fluoride on chondrocyte differentiation and the regulation of circadian clock signaling pathway during chondrogenesis, we treated ATDC5 cells with fluoride and carried out a series of experiments. 10-3 M fluoride inhibited cell viability and significantly decreased the expression of Sox9 and Col2a1 (P < 0.05). Fluoride inhibited proteoglycan synthesis and decreased significantly the expression of Aggrecan, Ihh and Col10a1 (P < 0.05). Meanwhile, fluoride significantly inhibited the expression of Bmal1 and disrupted circadian clock signaling pathway (P < 0.05). Furthermore, fluoride disrupted the time-dependent expression of circadian clock molecules and stage-specific differentiation markers. Overexpression of Bmal1 by lentivirus reversed the adverse effects of fluoride on chondrogenesis. These results suggested that fluoride inhibited chondrocyte viability and delayed chondrocyte differentiation. Fluoride delayed chondrogenesis partly via interfering with Bmal1 and circadian clock signaling pathway. Nevertheless, the specific mechanism of circadian clock in fluoride-induced cartilage damage needs to be further studied.

Dynamic Mach-Zehnder interferometer based on the lateral displacement of a point source array.

A dynamic Mach-Zehnder interferometer based on lateral displacement of a point source array is proposed. The point source array is generated by a point source and a phase grating, where four point sources are of identical intensity. The lateral displacement of each point source can be adjusted to introduce π/2 phase steps in the interferograms. With a specially designed lens array in the spatial split imaging system, four separated and clear imaging interferograms can be captured in a single shot. Using a four-bucket algorithm, the phase distribution can be retrieved exactly, thereby realizing dynamic measurement. The experimental results show the feasibility and high precision of this dynamic Mach-Zehnder interferometer.

Investigation of inter-subject variation in ultrafine particle deposition across human nasal airways: A study involving children, adults, and the elderly.

The airflow and particle dynamics in adult nasal airways have been extensively investigated, but the impact of age-related anatomical changes in children and the elderly remains underexplored. This study systematically investigates age-related anatomical variations and associated influence on nasal airflow dynamics and ultrafine particle deposition characteristics by using Computational Fluid-Particle Dynamics (CFPD) approach. Numerical simulations were conducted for 9 healthy nasal subjects spanning a wide age range. 6 Nasal subjects from the Development Group were used as the primary models for data analysis and deposition correlation development, while 3 subjects from the Validation Group were used to validate the reliability of the derived total and subregional deposition correlations. Our results reveal distinctive variations across age groups. Specifically, the elderly and children exhibit unique patterns that differ from those of young adults. While total deposition efficiency differs significantly between children and adults, filtration efficiency in the subregion with most deposition, main respiratory, remains consistent. Lastly, overall and subregional empirical equations for deposition efficiency were developed by incorporating the combined diffusion parameter, Sca∆b, corroborating the use of geometrical characteristic parameters for each specific subject in predicting nasal deposition efficiency across different age groups. Our findings are expected to improve the predictive nanoparticle exposure analysis in nasal airways across different age groups, thereby improving the respiratory health for individuals throughout the life span.

Numerical modelling of micron particle inhalation in a realistic nasal airway with pediatric adenoid hypertrophy: A virtual comparison between pre- and postoperative models.

Adenoid hypertrophy (AH) is an obstructive condition due to enlarged adenoids, causing mouth breathing, nasal blockage, snoring and/or restless sleep. While reliable diagnostic techniques, such as lateral soft tissue x-ray imaging or flexible nasopharyngoscopy, have been widely adopted in general practice, the actual impact of airway obstruction on nasal airflow and inhalation exposure to drug aerosols remains largely unknown. In this study, the effects of adenoid hypertrophy on airflow and micron particle inhalation exposure characteristics were analysed by virtually comparing pre- and postoperative models based on a realistic 3-year-old nasal airway with AH. More specifically, detailed comparison focused on anatomical shape variations, overall airflow and olfactory ventilation, associated particle deposition in overall and local regions were conducted. Our results indicate that the enlarged adenoid tissue can significantly alter the airflow fields. By virtually removing the enlarged tissue and restoring the airway, peak velocity and wall shear stress were restored, and olfactory ventilation was considerably improved (with a 16∼63% improvement in terms of local ventilation speed). Furthermore, particle deposition results revealed that nasal airway with AH exhibits higher particle filtration tendency with densely packed deposition hot spots being observed along the floor region and enlarged adenoid tissue area. While for the postoperative model, the deposition curve was shifted to the right. The local deposition efficiency results demonstrated that more particles with larger inertia can be delivered to the targeted affected area following Adenoidectomy (Adenoid Removal). Research findings are expected to provide scientific evidence for adenoidectomy planning and aerosol therapy following Adenoidectomy, which can substantially improve present clinical treatment outcomes.

Numerical comparison of inspiratory airflow patterns in human nasal cavities with distinct age differences.

As a primary determinant of nasal physiological functions, the nasal morphology and its effects on the airflow dynamics have been extensively studied in literature. However, gross flow features reported in literature are mostly obtained from subjects at similar ages, while studies focusing on nasal subjects with distinct age differences are significantly less. To advance current understandings of nasal airflow dynamics in the context of age diversity, this study employed three anatomically accurate nasal cavity models with distinct age features (5-, 24- and 77-year-old models) and numerically compared the physiological nasal airflow fields within these nasal cavity models. To demonstrate the validity of the present numerical models, in vivo rhinomanometry measurement was conducted on the 24-year-old female nasal model, and key anatomical features and pressure-flow curves of all three models were compared with models with similar age features in literature work. Apart from results comparison based on conventional velocity flow fields and wall shear stress distributions, a method for quantifying flow partitions in confined airway spaces was developed to reveal the proportions of fractional flow that enters the olfactory region. Our results revealed dramatic intersubject discrepancies between considered nasal cavity models, especially for the fractional flow that enters the olfactory region. Specifically, the 5-year-old girl nasal model received the highest proportion of fractional flow, which accounts for 13.3% ~ 15% of overall inhalation flow rates under different activity levels. For the 24-year-old female model, on the contrary, the olfactory fractional flow was dramatically reduced (with a local to overall percentage around 4.3%-7.7%). Finally, for the elderly subject-77-year-old male model, minimum level of olfactory flux was observed with a local to overall percentage ranging between 3.1% and 4.9% for considered wide range of inhalation flow rates. Therefore, the local flow intersubject variation can reach nearly fourfold. The vast local flow difference is mainly due to the inherent anatomical features (e.g., immature nasal turbinate structure in the child model, the partial narrowing superior nasal valve in the elder model). The results may further lead to discrepant health effects associated with inhalation exposure to airborne particles.

Fluoride regulates the expression of extracellular matrix HSPG and related signaling pathways FGFR3 and Ihh/PTHrP feedback loop during endochondral ossification.

Skeletal fluorosis causes growth plate impairment and growth retardation during bone development. Longitudinal bone development is accomplished by endochondral ossification in growth plate. However, the mechanism of fluoride impairs growth plate is unclear. To explore the effect of fluoride on various glycosaminoglycans (GAGs) and related signaling pathways in growth plate during endochondral ossification, SD rats and ATDC5 cells were treated with fluoride and carried out a series of experiments. We found that the expression of heparan sulfate (HS), a kind of GAGs in extracellular matrix, was significantly increased in the growth plate of fluoride-treated rats compared with control rats. Furthermore, the expression of HS synthetic enzyme exostosin 1 (EXT1) and glypican 6 (GPC6), a core protein of HS proteoglycan (HSPG), were significantly increased in fluoride-treated ATDC5 cells compared with control cells (P < 0.05). The expression of related molecules including fibroblast growth factor receptor-3 (FGFR3), signal transducer and activator of transcription 1 (STAT1) and parathyroid hormone-related protein (PTHrP) were significantly increased in the fluoride-treated groups compared with control groups (P < 0.05), and there was significantly decreased in the expression of Indian hedgehog (Ihh) in fluoride-treated groups compared with control groups (P < 0.05). Our data suggested that fluoride increased the content of HSPG in extracellular matrix by promoting the expression of EXT1 and GPC6. Fluoride also activated FGFR3 signaling pathway, inhibited Ihh/PTHrP feedback loop and inhibited endochondral ossification. Nevertheless, the regulation of fluoride on HSPG and related pathways FGFR3 and Ihh/PTHrP feedback loop during endochondral ossification needs to be further studied.

Speeding up Permutation Testing in Neuroimaging.

Multiple hypothesis testing is a significant problem in nearly all neuroimaging studies. In order to correct for this phenomena, we require a reliable estimate of the Family-Wise Error Rate (FWER). The well known Bonferroni correction method, while simple to implement, is quite conservative, and can substantially under-power a study because it ignores dependencies between test statistics. Permutation testing, on the other hand, is an exact, non-parametric method of estimating the FWER for a given α-threshold, but for acceptably low thresholds the computational burden can be prohibitive. In this paper, we show that permutation testing in fact amounts to populating the columns of a very large matrix P. By analyzing the spectrum of this matrix, under certain conditions, we see that P has a low-rank plus a low-variance residual decomposition which makes it suitable for highly sub-sampled - on the order of 0.5% - matrix completion methods. Based on this observation, we propose a novel permutation testing methodology which offers a large speedup, without sacrificing the fidelity of the estimated FWER. Our evaluations on four different neuroimaging datasets show that a computational speedup factor of roughly 50× can be achieved while recovering the FWER distribution up to very high accuracy. Further, we show that the estimated α-threshold is also recovered faithfully, and is stable.