Automated bidirectional coupling of multiscale models of aerosol dosimetry: validation with subject-specific deposition data.

Assessing the toxicity of airborne particulate matter or the efficacy of inhaled drug depends upon accurate estimates of deposited fraction of inhaled materials. In silico approaches can provide important insights into site- or airway-specific deposition of inhaled aerosols in the respiratory system. In this study, we improved on our recently developed 3D/1D model that simulate aerosol transport and deposition in the whole lung over multiple breath cycles (J. Aerosol Sci 151:105647). A subject-specific multiscale lung model of a healthy male subject using computational fluid-particle dynamics (CFPD) in a 3D model of the oral cavity through the large bronchial airways entering each lobe was bidirectionally coupled with a recently improved Multiple Path Particle Dosimetry (MPPD) model to predict aerosol deposition over the entire respiratory tract over multiple breaths for four conditions matching experimental aerosol exposures in the same subject from which the model was developed. These include two particle sizes (1 and 2.9 µm) and two subject-specific breathing rates of ~300 ml/s (slow breathing) and ~750 ml/s (fast breathing) at a target tidal volume of 1 L. In silico predictions of retained fraction were 0.31 and 0.29 for 1 µm and 0.66 and 0.62 for 2.9 µm during slow and fast breathing, respectively, and compared well with experimental data (1 µm: 0.31±0.01 (slow) and 0.27±0.01 (fast), 2.9 µm: 0.63±0.03 (slow) and 0.68±0.02 (fast)). These results provide a great deal of confidence in the validity and reliability of our approach.

Influence of alveolar mixing and multiple breaths of aerosol intake on particle deposition in the human lungs.

Predictive dosimetry models play an important role in assessing health effect of inhaled particulate matter and in optimizing delivery of inhaled pharmaceutical aerosols. In this study, the commonly used 1D Multiple-Path Particle Dosimetry model (MPPD) was improved by including a mechanistically based model component for alveolar mixing of particles and by extending the model capabilities to account for multiple breaths of aerosol intake. These modifications increased the retained fraction of particles and consequently particle deposition predictions in the deep lung during tidal breathing. Comparison with an existing dataset (J. Aerosol Sci., 99:27-39, 2016) obtained under two breathing conditions referred to as slow and fast breathing showed significant differences in 1 µm particle deposition between predictions based on subject-specific breathing patterns and lung volume (slow: 30 ± 1%, fast: 21 ± 1%, (average ± standard deviation), N = 7) and measurements (slow: 43 ± 9%, fast: 30 ± 5%) when the prior version of MPPD (single breath and no mixing, J. Aerosol Sci., 151:105647, 2021) was used. Adding a mixing model and multiple breaths moved the predictions (slow: 34 ± 2%, fast:25 ± 2%) closer to the range of deposition measurements. For 2.9 µm particles, predictions from both the original (slow: 70 ± 2%, fast: 57 ± 2%) and the revised MPPD model (slow: 71 ± 2%, fast: 59 ± 3%) compared well with experiments (slow: 67 ± 8%, fast: 58 ± 10%). This was expected as suspended fraction of 2.9 µm particles was small and thus the addition of alveolar mixing and multi breath capability only slightly increased the retained fraction for particles of this size and greater. The revised 1D model improves dose predictions in the deep lung and support human risk assessment from exposure to airborne particles.

Efficient bi-directional coupling of 3D Computational Fluid-Particle Dynamics and 1D Multiple Path Particle Dosimetry lung models for multiscale modeling of aerosol dosimetry.

The development of predictive aerosol dosimetry models has been a major focus of environmental toxicology and pharmaceutical health research for decades. One-dimensional (1D) models successfully predict overall deposition averages but fail to accurately predict local deposition. Computational fluid-particle dynamics (CFPD) models provide site-specific predictions but at a computational cost that prohibits whole lung predictions. Thus, there is a need for developing multiscale strategies to provide a realistic subject-specific picture of the fate of inhaled aerosol in the lungs. CT-based 3D/CFPD models of the large airways were bidirectionally coupled with individualized 1D Navier-Stokes airflow and particle transport based upon the widely used Multiple Path Particle Dosimetry Model (MPPD). Distribution of airflows among lobes was adjusted by measured lobar volume changes observed in CT images between FRC and FRC + 1.5 L. As a test of the effectiveness of the coupling procedures, deposition modeling of previous 1 µm aerosol exposure studies was performed. The complete coupled model was run for 3 breaths, with the computation-intense portion being the 3D CFPD Lagrangian particle tracking calculation. The average deposition per breath was 11% in the combined multiscale model with site-specific doses available in the CFPD portion of the model and airway- or region-specific deposition available for the MPPD portion. In conclusion, the key methods developed in this study enable predictions of ventilation heterogeneities and aerosol deposition across the lungs that are not captured by 3D or 1D models alone. These methods can be used as the foundation for multi-scale modeling of the full respiratory system.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

Computational fluid dynamics modeling of Bacillus anthracis spore deposition in rabbit and human respiratory airways.

Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived respectively from computed tomography (CT) and µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation-exhalation breathing conditions using average species-specific minute volumes. Two different exposure scenarios were modeled in the rabbit based upon experimental inhalation studies. For comparison, human simulations were conducted at the highest exposure concentration used during the rabbit experimental exposures. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the nasal sinus compared to the human at the same air concentration of anthrax spores. In contrast, higher spore deposition was predicted in the lower conducting airways of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology for deposition.

Stability and change of genetic and environmental effects on the common liability to alcohol, tobacco, and cannabis DSM-IV dependence symptoms.

This study investigated the stability of genetic and environmental effects on the common liability to alcohol, tobacco, and cannabis dependence across adolescence and young adulthood. DSM-IV symptom counts from 2,361 adolescents were obtained using a structured diagnostic interview. Several sex-limited longitudinal common pathway models were used to examine gender differences in the magnitude of additive genetic (A), shared environment, and non-shared environmental effects over time. Model fitting indicated limited gender differences. Among older adolescents (i.e., age > 14), the heritability of the latent trait was estimated at 0.43 (0.05, 0.94) during the first wave and 0.63 (0.21, 0.83) during the second wave of assessment. A common genetic factor could account for genetic influences at both assessments, as well as the majority of the stability of SAV over time [rA = 1.00 (0.55, 1.00)]. These results suggest that early genetic factors continue to play a key role at later developmental stages.

Extension of a PBPK model for ethylene glycol and glycolic acid to include the competitive formation and clearance of metabolites associated with kidney toxicity in rats and humans.

A previously developed PBPK model for ethylene glycol and glycolic acid was extended to include glyoxylic acid, oxalic acid, and the precipitation of calcium oxalate that is associated with kidney toxicity in rats and humans. The development and evaluation of the PBPK model was based upon previously published pharmacokinetic studies coupled with measured blood and tissue partition coefficients and rates of in vitro metabolism of glyoxylic acid to oxalic acid, glycine and other metabolites using primary hepatocytes isolated from male Wistar rats and humans. Precipitation of oxalic acid with calcium in the kidneys was assumed to occur only at concentrations exceeding the thermodynamic solubility product for calcium oxalate. This solubility product can be affected by local concentrations of calcium and other ions that are expressed in the model using an ion activity product estimated from toxicity studies such that calcium oxalate precipitation would be minimal at dietary exposures below the NOAEL for kidney toxicity in the sensitive male Wistar rat. The resulting integrated PBPK predicts that bolus oral or dietary exposures to ethylene glycol would result in typically 1.4-1.6-fold higher peak oxalate levels and 1.6-2-fold higher AUC's for calcium oxalate in kidneys of humans as compared with comparably exposed male Wistar rats over a dose range of 1-1000 mg/kg. The converse (male Wistar rats predicted to have greater oxalate levels in the kidneys than humans) was found for inhalation exposures although no accumulation of calcium oxalate is predicted to occur until exposures are well in excess of the theoretical saturated vapor concentration of 200mg/m(3). While the current model is capable of such cross-species, dose, and route-of-exposure comparisons, it also highlights several areas of potential research that will improve confidence in such predictions, especially at low doses relevant for most human exposures.

The heritability of general cognitive ability increases linearly from childhood to young adulthood.

Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite life's 'slings and arrows of outrageous fortune', do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype-environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.

Baseline brain function in the preadolescents of the ABCD Study.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development.

Regulated expression of mouse mammary tumor proviral genes in cells of the B lineage.

We evaluated the expression of mouse mammary tumor proviral (MMTV) transcripts during B cell ontogeny and compared levels of RNA in B lymphocytes and B cell lines with levels in other cells of the hematopoietic lineage and in a mammary cell line. We demonstrate that MMTV transcripts are expressed as early as the pro-B cell stage in ontogeny and are expressed at basal constitutive levels throughout most of the B cell developmental pathway. The level of MMTV expression in B cells is similar to constitutive levels in mammary tissues and two to three orders of magnitude greater than in activated T cells. Levels of MMTV transcripts in B cells are not solely due to positional effects. Transient transfection assays showed that MMTV upregulation resulted from transcriptional activation of the viral LTR, indicating that there are specific and inducible transcription factors that regulate MMTV expression in B cells. MMTV transcripts could not be upregulated in pre-B cell lines but could be induced in some mature B cell lines. There was a correlation between the ability to stimulate B cells to secrete antibody and the ability to induce upregulated MMTV expression. Evidence is presented that suggests that the principal transcription factors involved in MMTV expression do not include the B cell factors OTF-2 or NF-kappa B, but rather are likely to be novel factors that are induced during differentiation to antibody secretion. A hypothesis for why mammary tumor viruses are well adapted for expression in cells of the B lineage is proposed, and the implications of this for the documented influence of MMTV gene products on the T cell repertoire are discussed.

Regulation of B cell lymphomagenesis by a malignant Qal+ inducer T cell clone.

A series of Thy-1.2+ Ly-1+ Qa-1+ malignant T cell clones have been isolated from murine sarcoma virus-murine leukemia-Moloney (MSV-MuLV-M)-induced B cell lymphomas or from MSV-MuLV-M-infected B6 mice. These T cell clones enhance both antigen-independent and -dependent lymphocyte differentiation and function. They also induce the differentiation of granulocytes and erythrocytes in the stem cell compartment, a function that parallels the immunopathology of the disease in vivo. The malignant T cell appears to sustain B lymphoma growth in vivo by releasing a factor (BCGF) that promotes B cell proliferation.

Major histocompatibility complex-restricted recognition of retroviral superantigens by V beta 17+ T cells.

It has been established that at least some V beta 17+ T cells interact with an endogenous superantigen encoded by the murine retrovirus, Mtv-9. To analyze the role of major histocompatibility complex (MHC) class II molecules in presenting the Mtv-9 encoded superantigen, vSAG-9 to V beta 17+ hybridomas, a panel of nine hybridomas was tested for their ability to respond to A20/2J (H-2d) and LBK (H-2a) cells which had been transfected with the vSAG-9 gene. Whereas some of the hybridomas recognized vSAG-9 exclusively in the context of H-2a, other hybridomas recognized vSAG-9 exclusively in the context of H-2d or in the context of both H-2d and H-2a. These results suggest that: (a) the class II MHC molecule plays a direct role in the recognition of retroviral superantigen by T cells, rather than serving simply as a platform for presentation; and, (b) it is likely that components of the TCR other than V beta are involved in the vSAG-9/TCR/class II interaction.

Multiple pathways of T-T interaction in the generation of cytotoxic T lymphocytes to alloantigens.

The interaction of T helper (Th) cells with syngeneic and allogeneic cytotoxic T lymphocyte precursors (CTL.P) has been investigated. Unprimed and mixed lymphocyte culture-primed peripheral T cells were used as a source of Th. Thymocytes, which depend upon exogenous Th cells for activation, were used as a source of cytotoxic precursors. Data is presented that demonstrates that at least two pathways of T-T interaction can lead to the activation of cytotoxic lymphocytes. The first is an allogeneic effect, in which Th cells recognize and respond to alloantigens expressed on CTL.P. The second is the interaction of Th cells with syngeneic CTL.P, in which both cell types are thought to respond to alloantigens on stimulator cells. The latter interaction can be shown to be restricted by H-2-linked determinants when primed Th cells are used and allogeneic effects against thymocytes are minimized. Restricted interactions between unprimed Th cells and thymocyte CTL.P have never been observed. Mechanisms that may explain the difference between the interaction of unprimed and primed Th cells with CTL.P are discussed.

Endogenous superantigen expression is controlled by mouse mammary tumor proviral loci.

Superantigens are defined by their ability to stimulate T cells based predominantly on their V beta expression and ability to delete T cells in the thymus when expressed endogenously. We show here that the expression of one endogenous superantigen, Etc-1, is controlled by the expression of the open reading frame region of the 3' long terminal repeat of the mouse mammary tumor proviral gene, Mtv-9. We show that Mtv-8 controls a superantigen with similar specificity, and that both Mtv-8 and Mtv-9 stimulate some V beta 17+ T cells. A third provirus, Mtv-6, controls a superantigen with specificity for V beta 3. Data presented raise the possibility that endogenous superantigens may compete for class II molecules in a single B cell.

Boron: possible role in plant metabolism.

Leaves of boron-deficient oil palm showed a total absence of the leucoanthocyanins usually present, well before onset of pathological symptoms. The association of boron with flavonoid synthesis is consistent with the otherwise anomalous situation that this element is essential for higher plants but not for animals or lower plants.

A simple genetic basis for a complex psychological trait in laboratory mice.

Psychological traits are commonly inferred from covariation in sets of behavioral measures that otherwise appear to have little in common. Emotionality in mice is such a trait, defined here by covariation in activity and defecation in a novel environment and emergence into the open arms of an elevated plus maze. Behavioral and quantitative trait analyses were conducted on four measures obtained from 879 mice from an F2 intercross. Three loci, on murine chromosomes 1, 12, and 15, were mapped that influence emotionality. This trait, inferred from studies of strain, sex, and individual differences in rodents, may be related to human susceptibility to anxiety or neuroticism.

Magnetic resonance imaging and computational fluid dynamics (CFD) simulations of rabbit nasal airflows for the development of hybrid CFD/PBPK models.

The percentages of total airflows over the nasal respiratory and olfactory epithelium of female rabbits were calculated from computational fluid dynamics (CFD) simulations of steady-state inhalation. These airflow calculations, along with nasal airway geometry determinations, are critical parameters for hybrid CFD/physiologically based pharmacokinetic models that describe the nasal dosimetry of water-soluble or reactive gases and vapors in rabbits. CFD simulations were based upon three-dimensional computational meshes derived from magnetic resonance images of three adult female New Zealand White (NZW) rabbits. In the anterior portion of the nose, the maxillary turbinates of rabbits are considerably more complex than comparable regions in rats, mice, monkeys, or humans. This leads to a greater surface area to volume ratio in this region and thus the potential for increased extraction of water soluble or reactive gases and vapors in the anterior portion of the nose compared to many other species. Although there was considerable interanimal variability in the fine structures of the nasal turbinates and airflows in the anterior portions of the nose, there was remarkable consistency between rabbits in the percentage of total inspired airflows that reached the ethmoid turbinate region (approximately 50%) that is presumably lined with olfactory epithelium. These latter results (airflows reaching the ethmoid turbinate region) were higher than previous published estimates for the male F344 rat (19%) and human (7%). These differences in regional airflows can have significant implications in interspecies extrapolations of nasal dosimetry.

Lipopolysaccharide and dexamethasone induce mouse mammary tumor proviral gene expression and differentiation in B lymphocytes through distinct regulatory pathways.

Endogenous mouse mammary tumor virus (MMTV) proviral transcripts are up regulated during the normal course of B-lymphocyte differentiation. We report here that the regulatory mechanisms which lead to increased levels of MMTV transcripts in differentiating, lipopolysaccharide (LPS)-stimulated normal B cells and in the inducible B-cell lymphoma line CH12 are at least partially distinct from those controlling increases in immunoglobulin and J-chain gene expression. In studies designed to characterize the stimulatory pathways leading to MMTV expression in CH12 cells, we found that stimulation with either LPS or dexamethasone (Dex), a transcriptional activator of MMTV genes, induced not only MMTV expression but also differentiation to antibody secretion. Only Dex-induced and not LPS-induced MMTV expression and differentiation were inhibited by the glucocorticoid antagonist RU486, demonstrating that Dex and LPS stimulate B cells by distinct molecular pathways. Therefore, in B cells, MMTV expression can be regulated via either the conventional hormone receptor-dependent pathway or a hormone receptor-independent pathway. Furthermore, these results suggest that steroid stimulation of B cells can lead to alterations in the expression of other results suggest that steroid stimulation of B cells can lead to alterations in the expression of other steroid-responsive genes that can become involved in the process of B-cell differentiation.

Interleukin-5 (IL-5) and IL-6 define two molecularly distinct pathways of B-cell differentiation.

Interleukin-5 (IL-5) and IL-6 have both been reported to act as B-cell differentiation factors by stimulating activated B cells to secrete antibody. However, it has not been possible to directly compare the effects of these two lymphokines because of the lack of a suitable B-cell line capable of responding to both. We have identified a clonal, inducible B-cell lymphoma, CH12, that has this property. Both IL-5 and IL-6 can independently stimulate increases in steady-state levels of immunoglobulin and J-chain mRNA and proteins, and they both induce the differentiation of CH12 into high-rate antibody-secreting cells. Nevertheless, there are significant differences in the activities of these two lymphokines. First, while IL-6 acts only as a differentiation factor, IL-5 also augments the proliferation of CH12 cells. Second, the differentiation stimulated by IL-5 but not by IL-6 is partially inhibited by IL-4. Inhibition of IL-5-induced differentiation was not at the level of IL-5 receptor expression, since IL-4 did not inhibit IL-5-induced proliferation. Third, IL-5 but not IL-6 stimulated increased mouse mammary tumor proviral gene expression in CH12 cells. These results demonstrate that while both IL-5 and IL-6 may act as differentiation factors for B cells, they induce differentiation by using at least partially distinct molecular pathways. Our results also establish that B cells characteristic of a single stage of development can independently respond to IL-4, IL-5, and IL-6.

Incorporation of therapeutic interventions in physiologically based pharmacokinetic modeling of human clinical case reports of accidental or intentional overdosing with ethylene glycol.

Although occupational uses of the high production volume (HPV) chemical ethylene glycol (EG) have not been associated with adverse effects, there are case reports where humans have either intentionally or accidentally ingested large quantities of EG, primarily from antifreeze. The acute toxicity of EG can proceed through three stages, each associated with a different metabolite: central nervous system depression (ethylene glycol), cardiopulmonary effects associated with metabolic acidosis (glycolic acid), and ultimately renal toxicity (oxalic acid), depending on the total amounts consumed and the effectiveness of therapeutic interventions. A physiologically based pharmacokinetic (PBPK) model developed in a companion paper (Corley et al., 2005). Development of a physiologically based pharmacokinetic model for ethylene glycol and its metabolite, glycolic acid, in rats and humans. Toxicol. Sci., in press 2005) was refined in this study to include clinically relevant treatment regimens for EG poisoning such as hemodialysis or metabolic inhibition with either ethanol or fomepizole. Such modifications enabled the model to describe data from several human case reports, confirming the ability of the previous model to describe the pharmacokinetics of EG and its metabolite, glycolic acid, in humans across a broad range of doses and multiple exposure routes. By integrating the case report data sets with controlled studies in this PBPK model, it was demonstrated that fomepizole, if administered early enough in a clinical situation, can be more effective than ethanol or hemodialysis in preventing the metabolism of EG to more toxic metabolites. Hemodialysis remains an important option, however, if treatment is instituted after a significant amount of EG is metabolized or if renal toxicity has occurred.