Aerosols in Healthy and Emphysematous In Silico Pulmonary Acinar Rat Models

International audienceThere has been relatively little attention given on predicting particle deposition in the respiratory zone of the diseased lungs despite the high prevalence of chronic obstructive pulmonary disease (COPD). Increased alveolar volume and deterioration of alveolar septum, characteristic of emphysema, may alter the amount and location of particle deposition compared to healthy lungs, which is particularly important for toxic or therapeutic aerosols. In an attempt to shed new light on aerosol transport and deposition in emphysematous lungs, we performed numerical simulations in models of healthy and emphysematous acini motivated by recent experimental lobar-level data in rats~\citep{OakesEmp}. Compared to healthy acinar structures, models of emphysematous subacini were created by removing inter-septal alveolar walls and enhancing the alveolar volume in either a homogeneous or heterogeneous fashion. Flow waveforms and particle properties were implemented to match the experimental data. The occurrence of flow separation and recirculation within alveolar cavities was found in proximal generations of the healthy zones, in contrast to the radial-like airflows observed in the diseased regions. In agreement with experimental data, simulations point to particle deposition concentrations that are more heterogeneously distributed in the diseased models compared with the healthy one. Yet, simulations predicted less deposition in the emphysematous models in contrast to some experimental studies, a likely consequence due to the shallower penetration depths and modified flow topologies in disease compared to health. These spatial-temporal particle transport simulations provide new insight on deposition in the emphysematous acini and shed light on experimental observations

Aerosols in the lung: multi-domain transport and coupling

International audienceIn this paper, we present a framework that couples three-dimensional (3D) to one-dimensional (1D) transport models to predict particle deposition in the respiratory airways throughout respiration. During respiration, the time dependent flow rate and particle concentration can be passed between the domains (inspiration: 3D to 1D, expiration: 1D to 3D). This framework enables us to predict particle transport and deposition in the whole lung and throughout both inspiration and expiration

Distribution of Aerosolized Particles in Healthy and Emphysematous Rat Lungs: Comparison Between Experimental and Numerical Studies

International audienceIn silico models of airflow and particle deposition in the lungs are increasingly used to determine the therapeutic or toxic effects of inhaled aerosols. While computational methods have advanced significantly, relatively few studies have directly compared model predictions to experimental data. Furthermore, few prior studies have examined the influence of emphysema on particle deposition. In this work we performed airflow and particle simulations to compare numerical predictions to data from our previous aerosol exposure experiments. Employing an image-based 3D rat airway geometry, we first compared steady flow simulations to coupled 3D-0D unsteady simulations in the healthy rat lung. Then, in 3D-0D simulations, the influence of emphysema was investigated by matching disease location to the experimental study. In both the healthy unsteady and steady simulations, good agreement was found between numerical predictions of aerosol delivery and experimental deposition data. However, deposition patterns in the 3D geometry differed between the unsteady and steady cases. On the contrary, satisfactory agreement was not found between the numerical predictions and experimental data for the emphysematous lungs. This indicates that the deposition rate downstream of the 3D geometry is likely proportional to airflow delivery in the healthy lungs, but not in the emphysematous lungs. Including small airway collapse, variations in downstream airway size and tissue properties, and tracking particles throughout expiration may result in a more favorable agreement in future studies

Airflow and Particle Deposition Simulations in Health and Emphysema: From In Vivo to In Silico Animal Experiments

International audienceImage-based in-silico modeling tools provide detailed velocity and particle deposition data. However, care must be taken when prescribing boundary conditions to model lung physiology in health or disease, such as in emphysema. In this study, the respiratory resistance and compliance were obtained by solving an inverse problem; a 0D global model based on healthy and emphysematous rat experimental data. Multi-scale CFD simulations were performed by solving the 3D Navier Stokes equations in an MRI-derived rat geometry coupled to a 0D model. Particles with 0.95 um diameter were tracked and their distribution in the lung was assessed. Seven 3D-0D simulations were performed: healthy, homogeneous, and five heterogeneous emphysema cases. Compliance (C) was significantly higher (p = 0.04) in the emphysematous rats (C = 0.37 +/- 0.14 cm^3 / cmH_2O) compared to the healthy rats (C = 0.25 +/- 0 0.04 cm^3 / cmH_2O), while the resistance remained unchanged (p = 0.83). There were increases in airflow, particle deposition in the 3D model, and particle delivery to the diseased regions for the heterogeneous cases compared to the homogeneous cases. The results highlight the importance of multi-scale numerical simulations to study airflow and particle distribution in healthy and diseased lungs. The effect of particle size and gravity were studied. Once available, these in-silico predictions may be compared to experimental deposition data

False negative results from using common PCR reagents

Background\ud The sensitivity of the PCR reaction makes it ideal for use when identifying potentially novel viral infections in human disease. Unfortunately, this same sensitivity also leaves this popular technique open to potential contamination with previously amplified PCR products, or "carry-over" contamination. PCR product carry-over contamination can be prevented with uracil-DNA-glycosylase (UNG), and it is for this reason that it is commonly included in many commercial PCR master-mixes. While testing the sensitivity of PCR assays to detect murine DNA contamination in human tissue samples, we inadvertently discovered that the use of this common PCR reagent may lead to the production of false-negative PCR results.\ud \ud Findings\ud We show here that contamination with minute quantities of UNG-digested PCR product or any negative control PCR reactions containing primer-dimers regardless of UNG presence can completely block amplification from as much as 60 ng of legitimate target DNA.\ud \ud Conclusions\ud These findings could potentially explain discrepant results from laboratories attempting to amplify MLV-related viruses including XMRV from human samples, as none of the published reports used internal-tube controls for amplification. The potential for false negative results needs to be considered and carefully controlled in PCR experiments, especially when the target copy number may be low - just as the potential for false positive results already is

Long-Term Infection and Vertical Transmission of a Gammaretrovirus in a Foreign Host Species

Increasing evidence has indicated natural transspecies transmission of gammaretroviruses; however, viral-host interactions after initial xeno-exposure remain poorly understood. Potential association of xenotropic murine leukemia virus-related virus (XMRV) in patients with prostate cancer and chronic fatigue syndrome has attracted broad interests in this topic. Although recent studies have indicated that XMRV is unlikely a human pathogen, further understanding of XMRV xenoinfection would allow in vivo modeling of the initial steps of gammaretroviral interspecies transmission, evolution and dissemination in a new host population. In this study, we monitored the long-term consequences of XMRV infection and its possible vertical transmission in a permissive foreign host, wild-derived Mus pahari mice. One year post-infection, XMRV-infected mice showed no notable pathological changes, while proviral DNA was detected in three out of eight mice. XMRV-infected mice remained seropositive throughout the study although the levels of gp70 Env- and p30 capsid-specific antibodies gradually decreased. When vertical XMRV transmission was assessed, no viremia, humoral immune responses nor endogenization were observed in nine offspring from infected mothers, yet one offspring was found PCR-positive for XMRV-specific sequences. Amplified viral sequences from the offspring showed several mutations, including one amino acid deletion in the receptor binding domain of Env SU. Our results therefore demonstrate long-term asymptomatic infection, low incidence of vertical transmission and limited evolution of XMRV upon transspecies infection of a permissive new host, Mus pahari

Broadband Multi-wavelength Properties of M87 during the 2017 Event Horizon Telescope Campaign

Abstract: In 2017, the Event Horizon Telescope (EHT) Collaboration succeeded in capturing the first direct image of the center of the M87 galaxy. The asymmetric ring morphology and size are consistent with theoretical expectations for a weakly accreting supermassive black hole of mass ∼6.5 × 109 M ⊙. The EHTC also partnered with several international facilities in space and on the ground, to arrange an extensive, quasi-simultaneous multi-wavelength campaign. This Letter presents the results and analysis of this campaign, as well as the multi-wavelength data as a legacy data repository. We captured M87 in a historically low state, and the core flux dominates over HST-1 at high energies, making it possible to combine core flux constraints with the more spatially precise very long baseline interferometry data. We present the most complete simultaneous multi-wavelength spectrum of the active nucleus to date, and discuss the complexity and caveats of combining data from different spatial scales into one broadband spectrum. We apply two heuristic, isotropic leptonic single-zone models to provide insight into the basic source properties, but conclude that a structured jet is necessary to explain M87’s spectrum. We can exclude that the simultaneous γ-ray emission is produced via inverse Compton emission in the same region producing the EHT mm-band emission, and further conclude that the γ-rays can only be produced in the inner jets (inward of HST-1) if there are strongly particle-dominated regions. Direct synchrotron emission from accelerated protons and secondaries cannot yet be excluded

Aerosol Deposition in Healthy and Emphysematous Rat Lungs : : Insights From MRI Measurements and Computational Simulations

Understanding the fate of inhaled aerosol particles in healthy and diseased lungs may help in assessing the toxic health effects of airborne particulate matter or the efficiency of therapeutic drugs delivered through the lung. This dissertation focused on determining aerosol particle deposition patterns in healthy and emphysematous rats lungs by utilizing experimental and numerical methods. In the experimental part of the study, both airway morphometry and deposition patterns were determined by MRI. In the morphometry study, healthy rat lungs were imaged in vivo. Airway geometries were extracted from the MR images and the morphometric dimensions were validated against previous studies. In the aerosol deposition study, healthy and emphysematous rats were exposed by mechanical ventilation to iron-oxide particles with 1.22[mu]m mass mean aerodynamic diameter (MMAD). The lungs were imaged with a MR gradient echo sequence and the signal decay rate, R*₂, was calculated from the signal intensity images. Data showed a significantly higher R*₂ in the rats exposed to particles than in the control rats (no aerosol exposure) both for the healthy and emphysematous groups. A calibration experiment showed that concentration of deposited particles in tissue samples was linearly related to R*₂. Particle concentration and relative dispersion of particle deposition sites in all lung lobes tended to be higher in the emphysematous rats compared to the healthy rats. To further study particle deposition sites in the rat lungs, multi-scale computational fluid dynamics (CFD) simulations were performed. The global resistance and compliance of the rat lungs were determined by solving a global resistance/compliance (RC) model. This same RC model was then employed as Neumann boundary conditions in the 0D-3D simulations. Deposition and distribution of particles to the rat lobes was determined for particles with the same diameter as those used in the experiments. Simulations were performed representing healthy, homogeneous and localized emphysema. Emphysema location was determined by utilizing findings from the experimental data. Deposition in the 3D model was higher in the emphysematous cases compared to the healthy cases. Additionally, there was an increase in delivery of particle-laden air to the diseased regions of the lung, compared to the healthy regions. Good agreement was found when comparing the simulated normalized delivery of particles to each lobe to the normalized experimental deposition data. This work is the first to compare deposition sites found numerically and experimentally in both healthy and emphysematous lungs. In future studies, the multi-scale CFD models developed here may be advanced to include particle tracking downstream of the 3D mode

The Cat is Out of the Bag: Previous Experience and Online Comparison Jointly Influence Infant Categorization.

We examined the effect of 4-month-old infants previous experience with dogs and/or cats and their on-line comparison on their learning of the adult-defined category of cat in a visual familiarization task. In Experiment 1, 4-month-old infants (N=97) learning in the laboratory was jointly determined by whether or not they had experience with pets at home and their level of on-line comparison during familiarization. Specifically, only infants with pets at home who were also high comparers during familiarization remembered the individual cat exemplars or formed a summary representation of those cats. In Experiments 2 and 3, 4-month-old infants (N = 33) who were low comparers and/or did not have pets at home failed to discriminate among the individual items. These results are consistent with recent theorizing about the processes of how infants categorical representations are formed, and provide new understanding into how infants categorization unfolds over time