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The purpose of this paper is to review the application of mathematical models of inhaled particle deposition to people of various ages. The basic considerations of aerosol physics, biological characteristics and model structure are presented along with limitations inherent in modern modeling techniques. Application of the models to children and senescent adults has been largely based on extrapolating anatomical and physiological data from young adults to match the changes observed during growth and aging. Sample results are included for total particle deposition and deposition in the bronchial and pulmonary regions. The models proposed provide particle deposition predictions that are consistent with the scant measurements available. The models discussed appear to be on firm theoretical grounds, but they are largely limited in application to simple aerosols and average individuals. Also, additional validation of the computational predictions is needed.

An area identified as having a high priority by the National Research Council (NRC 1998) relating to health effects of exposure to urban particulate matter is the investigation of particle deposition patterns in potentially-susceptible subpopulations. A key task for risk assessment is development and refinement of mathematical models that predict local deposition patterns of inhaled particles in airways. Recently, computational fluid dynamic modeling (CFD) has provided the ability to predict local airflows and particle deposition patterns in various structures of the human respiratory tract. Although CFD results generally agree with available data from human studies, there is a need for experimental particle deposition investigations that provide more detailed comparisons with computed local patterns of particle deposition. Idealized 3-generation hollow tracheobronchial models based on the Weibel symmetric morphometry for airway lengths and diameters (generations 3-5) were constructed with physiologically-realistic bifurcations. Monodisperse fluorescent polystyrene latex particles (1 and 10 μm aerodynamic diameter) were deposited in these models at a steady inspiratory flow of 7.5 L/min (equivalent to heavy exertion with a tracheal flow of 60 L/min). The models were opened and the locations of deposited particles were mapped using fluorescence microscopy. The particle deposition predictions using CFD for 10 μm particles correlated well with those found experimentally. CFD predictions were not available for the 1 μm diameter case, but the experimental results for such particles are presented.

The effects of variations in cyclic breathing parameters (i.e., tidal volume and breath frequency) have been the subject of few studies devoted to the deposition of submicrometer aerosols in the human respiratory tract. Therefore, a series of experiments was performed to investigate whether the deposition efficiency (DE) of sidestream cigarette smoke is altered by varying tidal volume and breath frequency in a child-size hollow tracheobronchial (TB) model while maintaining a fixed minute ventilation rate of 5 L/min. Under cyclic flow conditions with tidal volumes of 100 mL (50 breaths/min), 250 mL (20 breaths/min), 500 mL (10 breaths/min) and 750 mL (6.7 breaths/min), sidestream cigarette smoke was passed through replicas of an idealized hollow TB model. The smoke deposits were extracted and then quantitated spectrophotometrically. The experiments revealed a significant difference in DE between the 100-mL tidal volume (DE = 6.0%) and the 750-mL tidal volume (DE = 11.1%). Under equivalent steady flow conditions, the mean DE was 21.5%. A trend was evident in the data--DE increased as tidal volume increased (and breathing frequency decreased)--suggesting that the influence of diffusion and secondary flows on DE becomes greater as the air residence time increases and the degree of air turbulence decreases. The results provide evidence of the importance of breathing parameters when attempting to model in vivo deposition of environmental tobacco smoke and other similar-size respirable aerosols.

This study assessed the effects of repeated exposure to environmentally realistic levels of two urban air pollutants nitric acid vapor (HNO3) and ozone (O3) - on tracer particle clearance from the rat respiratory tract. The measurement of particle clearance efficiency is important because failure of this function could contribute to a buildup of foreign matter in the respiratory tract. Separate groups of rats (30 rats per group) were exposed nose-only for 4 h/day, 3 days/wk (a surrogate for an air pollution episode) for 40 wk to 4 atmospheres: purified air; 0.15 ppm O3; 50 μg/m3 HNO3; and 0.15 ppm O3 + 50 μg/m3 HNO3. At 4 wk prior to the end of the exposure, the rats inhaled radiolabeled tracer particles nose-only for 30 min. A clearance measurement protocol was then followed to estimate the rates of early and late clearance. Early (presumably upper respiratory tract) clearance was monitored during the 48 h following tracer deposition by the analysis of radioactivity excreted in the feces, while late (presumably deep lung) clearance was characterized by a combination of chest counting and 30 day postexposure sacrifice radioactivity analyses. The exposure to O3, both alone and in combination with HNO3, produced a more than 30% (statistically significant) delay during the initial phase of upper respiratory tract clearance, and all of the pollutant exposures may have stimulated deep lung clearance. The directions of these effects were the same as those observed previously when rats were acutely exposed to O3- containing atmospheres.

It has been suggested that highly concentrated aerosols exhibit colligative behavior due to hydrodynamic interactions among particles. Such behavior includes enhanced settling rates (cloud settling) and possibly increased deposition efficiency upon inhalation. The purpose of our study was to determine whether or not concentrated sidestream cigarette smoke would deposit in an enhanced manner in hollow models that represented human nasal airways. Sidestream smoke wisps were generated by smoldering 1R3 University of Kentucky research cigarettes and were drawn horizontally through the models. The smoke aerosol had a mass median aerodynamic diameter of about 0.45 μm and a geometric standard deviation of about 1.3. Photographs indicated that the smoke consisted primarily of wisps that had characteristic diameters of about 0.3 mm and lengths that were typically greater than 1 cm. These wisps, which were surrounded by relatively particle-free air, were the entities that might exhibit cloud-like behavior. The average measured percentage deposition efficiency of cigarette smoke in the nasal casts was 4.5 ± 0.2 (SE). This value is close to what one would expect for particles of 0.45 μm aerodynamic diameter. Colligative behavior did not appear to produce measurably enhanced deposition in the surrogate nasal models. © 1994.

During growth and development, young children are periodically exposed to relatively high concentrations of various air contaminants, including tobacco smoke and environmental pollutants generated by fossil fuel use. The effects of these exposures on respiratory function and lung development are difficult to determine because of interindividual variation and lack of accurate dosimetry. To provide information on the effects of chronic exposure to a common indoor and outdoor pollutant during lung development, a study was performed to assess the effects of exposure to two concentrations of nitrogen dioxide (NO2; 0.5 or 10 ppm) on tracer particle clearance from the airways of ferrets exposed during postnatal respiratory tract development. Separate groups of ferrets were exposed nose-only to the test atmospheres or clean air 4 h/d, 5 d/wk, for either 8 or 15 wk. Those animals exposed for 8 wk were subsequently housed in a filtered air environment until the particle clearance measurements commenced at 3 wk prior to the end of the 15-wk exposure protocol. Radiolabeled (51Cr) tracer particles were deposited in the respiratory tract of all animals by inhalation, and the clearance rates from the head and thoracic regions were separately monitored for 18 d. No significant effects of the NO2 exposure on head airways clearance were seen. In contrast, the rates of particle clearance from the thorax of both the 8- and 15-wk groups exposed to 10 ppm NO2 were significantly reduced, and did not differ from each other. Thoracic clearance was also reduced in animals exposed to 0.5 ppm, but the rate was not significantly different from that of the clean air exposed controls. These results show that NO2 at moderate concentrations caused highly significant changes in the deep lung of the juvenile ferret, and suggest that impairment of the clearance function may be only slowly recovered after chronic exposure.

A series of cigarette smoke deposition studies was performed that used hollow models designed to represent the upper airways of adults and children. A major objective of the studies was to look for evidence of the influence of the colligative behavior of concentrated smoke on deposition in the hollow models. Another objective was to identify possible body-size—related factors in cigarette smoke deposition. The concentrated sidestream smoke from 1R3 University of Kentucky unfiltered research cigarettes was drawn through three sizes of airway-like hollow models at flow rates representing resting levels of physical exertion. The models, made of silicone rubber, represented the pharynx, larynx, and first three or four generations of the tracheobronchial airways. The models were scaled in size to represent young adults, 7-year-olds, and 4-year-olds. After smoke deposition, the models were cut into smaller pieces which were ultra sonically agitated in isopropyl alcohol, and the recovered deposits were analyzed spectrophotometrically (at a wavelength of 350 nm). Through the additional analysis of exit filters behind the models, smoke deposition efficiency was quantified. The study was unable to detect any significant effects of body size on the deposition efficiency of smoke. However, significant increases in deposition over those predicted (using accepted deposition models) for submicrometer particles were observed in all casts. The enhanced deposition could be attributed to the colligative behavior of smoke. In fact, the smoke aerosols, which had submicrometer diameter primary particles, deposited in the tracheobronchial trees as if they were between 6 and 7 μm in aerodynamic diameter. © 1994 Elsevier Science Inc.

This study was performed to assess the effects of two high concentrations (about 380 mg/m3 and about 38 mg/m3) of inhaled cigarette smoke on tracer particle clearance from the head airways region and the thoracic (primarily deep lung) region of ferrets exposed during postnatal respiratory tract development. Ferrets were exposed 2 h/days, 5 days/wk to purified air or to the smoke aerosols starting at 5 wk of age, for a total of 15 wk of exposure. Three weeks prior to the end of the 15-wk exposure regimen, radiolabeled tracer particles were deposited by inhalation, and the clearance rates from the head airways and thoracic regions were monitored for 18 days. The head airways counting data were accurately fit by a double exponential function, reflecting fast-clearing and slow-clearing components. The thoracic counting data were adequately fit by a single exponential function. Statistically significant accelerations of particle clearance rates were observed for the slow-clearing and fast-clearing phases of clearance from the head airways region for both the higher and lower concentration groups; the results implied a dose-response relationship. Only in the case of the higher concentration group was significant slowing observed in the thoracic region analysis, indicating that the head airways region was perhaps the area of greater impact of the smoke aerosol. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

A method is described for preparing fully-inflated whole lung specimens that are suitable for instruction or research purposes. Undamaged lungs are removed from the body and then tracheally cannulated and lavaged with tap water more than 250 times. The treatment also includes rinsing blood from vessels with water. A final filling of the lung with alcohol is optional. The multiply rinsed lung is drained and inflated to 30 cm of H2O pressure with dehumidified air and held at that pressure until the tissue is completely dry. The resulting specimens are light in color and appear to be permanent if stored properly.

Mathematical predictions of inhaled particle deposition patterns are widely used for evaluating hazards, modeling respiratory tract physiology and designing aerosol medical procedures. The parameters that are used in aerosol deposition models are physical and biological factors including those associated with the suspended particles, the suspending medium, the gravitational force field, the ventilatory airflow and the respiratory tract airways. It is useful to know how each parameter influences the predicted particle deposition in a calculation; that is, how sensitive the prediction is to a variation in each parameter. With such sensitivity information one a) might better estimate the required accuracy and precision of the input parameters for a calculation, and b) can develop new insights into inhaled particle phenomena in humans. Our sensitivity analysis covered deposition efficiency in the tracheobronchial region only during inspiration. We used a mathematical deposition model published by Yeh and Schum (1980) and our 16 generation airway model (Phalen et al., 1985). The analysis involved varying one model parameter at a time about a pre-selected nominal value. The following parameters were varied: particle diameter; particle density; viscosity of air; acceleration due to gravity; air flow rate; airway lengths; airway radii; airway branch angles; and airway gravity angles. Each analysis was performed for three particle diameters (0.1, 1.0 and 10 micrometers) and two subject ages (2 and 18 years). The results indicated that variations in each of the parameters can produce significant changes in particle deposition, but the most sensitive parameters were particle diameter and density, air flow rate, and airway lengths and radii. © 1991, Mary Ann Liebert, Inc. All rights reserved.

Cellular immunity against viral infection and tumour cells depends on antigen presentation by major histocompatibility complex class I (MHC I) molecules. Intracellular antigenic peptides are transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) and then loaded onto the nascent MHC I molecules, which are exported to the cell surface and present peptides to the immune system (1). Cytotoxic T lymphocytes recognize non-self peptides and program the infected or malignant cells for apoptosis. Defects in TAP account for immunodeficiency and tumour development. To escape immune surveillance, some viruses have evolved strategies either to downregulate TAP expression or directly inhibit TAP activity. So far, neither the architecture of TAP nor the mechanism of viral inhibition has been elucidated at the structural level. Here we describe the cryo-electron microscopy structure of human TAP in complex with its inhibitor ICP47, a small protein produced by the herpes simplex virus I. Here we show that the 12 transmembrane helices and 2 cytosolic nucleotide-binding domains of the transporter adopt an inward-facing conformation with the two nucleotide-binding domains separated. The viral inhibitor ICP47 forms a long helical hairpin, which plugs the translocation pathway of TAP from the cytoplasmic side. Association of ICP47 precludes substrate binding and prevents nucleotide-binding domain closure necessary for ATP hydrolysis. This work illustrates a striking example of immune evasion by persistent viruses. By blocking viral antigens from entering the endoplasmic reticulum, herpes simplex virus is hidden from cytotoxic T lymphocytes, which may contribute to establishing a lifelong infection in the host., Inside our body, every nucleated cell has surface 'barcodes' that are surveyed by the immune system. These barcodes are peptides derived from intracellular proteins, presented on the surface by MHC [...]

Author(s): Jan H. Lui [1]; Tomasz J. Nowakowski [1]; Alex A. Pollen [1]; Ashkan Javaherian [1]; Arnold R. Kriegstein (corresponding author) [1]; Michael C. Oldham (corresponding author) [1] Evolutionary expansion [...]

Oligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols (Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts. [ABSTRACT FROM AUTHOR]

Efficient carbon utilization is critical to the survival of microorganisms in competitive environments. To optimize energy usage, bacteria have developed an integrated control system to preferentially uptake carbohydrates that support rapid growth. The availability of a preferred carbon source, such as glucose, represses the synthesis and activities of proteins necessary for the transport and metabolism of secondary carbon sources. This regulatory phenomenon is defined as carbon catabolite repression1. In enteric bacteria, the key player of carbon catabolite repression is a component of the glucose-specific phosphotransferase system, enzyme IIA ([EIIA.sup.Glc]) (1,2). It is known that unphosphorylated [EIIA.sup.Glc] binds to and inhibits a variety of transporters when glucose is available (1,2). However, understanding the underlying molecular mechanism has been hindered by the complete absence of structures for any [EIIA.sup.Glc]--transporter complexes. Here we present the 3.9 Å crystal structure of Escherichia coli [EIIA.sup.Glc] in complex with the maltose transporter, an ATP-binding cassette (ABC) transporter. The structure shows that two [EIIA.sup.Glc] molecules bind to the cytoplasmic ATPase subunits, stabilizing the transporter in an inward-facing conformation and preventing the structural rearrangements necessary for ATP hydrolysis. We also show that the half-maximal inhibitory concentrations of the full-length [EIIA.sup.Glc] and an amino-terminal truncation mutant differ by 60-fold, consistent with the hypothesis that the amino-terminal region, disordered in the crystal structure, functions as a membrane anchor to increase the effective [EIIA.sup.Glc] concentration at the membrane (3,4). Together these data suggest a model of how the central regulatory protein [EIIA.sup.Glc] allosterically inhibits maltose uptake in E. coli., Carbon catabolite repression (CCR) is common in bacteria and higher organisms: up to 5-10% of all bacterial genes are subject to CCR regulation (1). Different organisms use different pathways to [...]