Mechanisms of injury due to intense plus G sub z vibration in water-immersed cats.
Mechanisms of lung injury due to intense vibration in water-immersed cats in upright position
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Bayesian estimation of dose thresholds
An example is described of Bayesian estimation of radiation absorbed dose thresholds (subsequently simply referred to as dose thresholds) using a specific parametric model applied to a data set on mice exposed to 60Co gamma rays and fission neutrons. A Weibull based relative risk model with a dose threshold parameter was used to analyse, as an example, lung cancer mortality and determine the posterior density for the threshold dose after single exposures to 60Co gamma rays or fission neutrons from the JANUS reactor at Argonne National Laboratory. The data consisted of survival, censoring times and cause of death information for male B6CF1 unexposed and exposed mice. The 60Co gamma whole-body doses for the two exposed groups were 0.86 and 1.37 Gy. The neutron whole-body doses were 0.19 and 0.38 Gy. Marginal posterior densities for the dose thresholds for neutron and gamma radiation were calculated with numerical integration and found to have quite different shapes. The density of the threshold for 60Co is unimodal with a mode at about 0.50 Gy. The threshold density for fission neutrons declines monotonically from a maximum value at zero with increasing doses. The posterior densities for all other parameters were similar for the two radiation types.
NASA Discipline Radiation Health↗
Association of particulate air pollution and acute mortality: involvement of ultrafine particles?
Recent epidemiological studies show an association between particulate air pollution and acute mortality and morbidity down to ambient particle concentrations below 100 micrograms/m3. Whether this association also implies a causality between acute health effects and particle exposure at these low levels is unclear at this time; no mechanism is known that would explain such dramatic effects of low ambient particle concentrations. Based on results of our past and most recent inhalation studies with ultrafine particles in rats, we propose that such particles, that is, particles below approximately 50 nm in diameter, may contribute to the observed increased mortality and morbidity In the past we demonstrated that inhalation of highly insoluble particles of low intrinsic toxicity, such as TiO2, results in significantly increased pulmonary inflammatory responses when their size is in the ultrafine particle range, approximately 20 nm in diameter. However, these effects were not of an acute nature and occurred only after prolonged inhalation exposure of the aggregated ultrafine particles at concentrations in the milligrams per cubic meter range. In contrast, in the course of our most recent studies with thermodegradation products of polytetrafluoroethylene (PTFE) we found that freshly generated PTFE fumes containing singlet ultrafine particles (median diameter 26 nm) were highly toxic to rats at inhaled concentrations of 0.7-1.0 x 10(6) particles/cm3, resulting in acute hemorrhagic pulmonary inflammation and death after 10-30 min of exposure. We also found that work performance of the rats in a running wheel was severely affected by PTFE fume exposure. These results confirm reports from other laboratories of the highly toxic nature of PTFE fumes, which cannot be attributed to gas-phase components of these fumes such as HF, carbonylfluoride, or perfluoroisobutylene, or to reactive radicals. The calculated mass concentration of the inhaled ultrafine PTFE particles in our studies was less than 60 micrograms/m3, a very low value to cause mortality in healthy rats. Aging of the fumes with concomitant aggregation of the ultrafine particles significantly decreases their toxicity. Since ultrafine particles are always present in the urban atmosphere, we suggest that they play a role in causing acute lung injury in sensitive parts of the population.
NASA Discipline Environmental Health↗
Alterations of p53 in tumorigenic human bronchial epithelial cells correlate with metastatic potential
The cellular and molecular mechanisms of radiation-induced lung cancer are not known. In the present study, alterations of p53 in tumorigenic human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells induced by a single low dose of either alpha-particles or 1 GeV/nucleon (56)Fe were analyzed by PCR-single-stranded conformation polymorphism (SSCP) coupled with sequencing analysis and immunoprecipitation assay. A total of nine primary and four secondary tumor cell lines, three of which were metastatic, together with the parental BEP2D and primary human bronchial epithelial (NHBE) cells were studied. The immunoprecipitation assay showed overexpression of mutant p53 proteins in all the tumor lines but not in NHBE and BEP2D cells. PCR-SSCP and sequencing analysis found band shifts and gene mutations in all four of the secondary tumors. A G-->T transversion in codon 139 in exon 5 that replaced Lys with Asn was detected in two tumor lines. One mutation each, involving a G-->T transversion in codon 215 in exon 6 (Ser-->lle) and a G-->A transition in codon 373 in exon 8 (Arg-->His), was identified in the remaining two secondary tumors. These results suggest that p53 alterations correlate with tumorigenesis in the BEP2D cell model and that mutations in the p53 gene may be indicative of metastatic potential.
Non-NASA Center↗
System identification of closed-loop cardiovascular control mechanisms: diabetic autonomic neuropathy
We applied cardiovascular system identification (CSI) to characterize closed-loop cardiovascular regulation in patients with diabetic autonomic neuropathy (DAN). The CSI method quantitatively analyzes beat-to-beat fluctuations in noninvasively measured heart rate, arterial blood pressure (ABP), and instantaneous lung volume (ILV) to characterize four physiological coupling mechanisms, two of which are autonomically mediated (the heart rate baroreflex and the coupling of respiration, measured in terms of ILV, to heart rate) and two of which are mechanically mediated (the coupling of ventricular contraction to the generation of the ABP wavelet and the coupling of respiration to ABP). We studied 37 control and 60 diabetic subjects who were classified as having minimal, moderate, or severe DAN on the basis of standard autonomic tests. The autonomically mediated couplings progressively decreased with increasing severity of DAN, whereas the mechanically mediated couplings were essentially unchanged. CSI identified differences between the minimal DAN and control groups, which were indistinguishable based on the standard autonomic tests. CSI may provide a powerful tool for assessing DAN.
Non-NASA Center↗
Human heart rate variability relation is unchanged during motion sickness
In a study of 18 human subjects, we applied a new technique, estimation of the transfer function between instantaneous lung volume (ILV) and instantaneous heart rate (HR), to assess autonomic activity during motion sickness. Two control recordings of ILV and electrocardiogram (ECG) were made prior to the development of motion sickness. During the first, subjects were seated motionless, and during the second they were seated rotating sinusoidally about an earth vertical axis. Subjects then wore prism goggles that reverse the left-right visual field and performed manual tasks until they developed moderate motion sickness. Finally, ILV and ECG were recorded while subjects maintained a relatively constant level of sickness by intermittent eye closure during rotation with the goggles. Based on analyses of ILV to HR transfer functions from the three conditions, we were unable to demonstrate a change in autonomic control of heart rate due to rotation alone or due to motion sickness. These findings do not support the notion that moderate motion sickness is manifested as a generalized autonomic response.
NASA Discipline Neuroscience↗
Linear and nonlinear ARMA model parameter estimation using an artificial neural network
This paper addresses parametric system identification of linear and nonlinear dynamic systems by analysis of the input and output signals. Specifically, we investigate the relationship between estimation of the system using a feedforward neural network model and estimation of the system by use of linear and nonlinear autoregressive moving-average (ARMA) models. By utilizing a neural network model incorporating a polynomial activation function, we show the equivalence of the artificial neural network to the linear and nonlinear ARMA models. We compare the parameterization of the estimated system using the neural network and ARMA approaches by utilizing data generated by means of computer simulations. Specifically, we show that the parameters of a simulated ARMA system can be obtained from the neural network analysis of the simulated data or by conventional least squares ARMA analysis. The feasibility of applying neural networks with polynomial activation functions to the analysis of experimental data is explored by application to measurements of heart rate (HR) and instantaneous lung volume (ILV) fluctuations.
NASA Discipline Regulatory Physiology↗
Alveolar ventilation to perfusion heterogeneity and diffusion impairment in a mathematical model of gas exchange
This study describes a two-compartment model of pulmonary gas exchange in which alveolar ventilation to perfusion (VA/Q) heterogeneity and impairment of pulmonary diffusing capacity (D) are simultaneously taken into account. The mathematical model uses as input data measurements usually obtained in the lung function laboratory. It consists of two compartments and an anatomical shunt. Each compartment receives fractions of alveolar ventilation and blood flow. Mass balance equations and integration of Fick's law of diffusion are used to compute alveolar and blood O2 and CO2 values compatible with input O2 uptake and CO2 elimination. Two applications are presented. The first is a method to partition O2 and CO2 alveolar-arterial gradients into VA/Q and D components. The technique is evaluated in data of patients with chronic obstructive pulmonary disease (COPD). The second is a theoretical analysis of the effects of blood flow variation in alveolar and blood O2 partial pressures. The results show the importance of simultaneous consideration of D to estimate VA/Q heterogeneity in patients with diffusion impairment. This factor plays an increasing role in gas alveolar-arterial gradients as severity of COPD increases. Association of VA/Q heterogeneity and D may produce an increase of O2 arterial pressure with decreasing QT which would not be observed if only D were considered. We conclude that the presented computer model is a useful tool for description and interpretation of data from COPD patients and for performing theoretical analysis of variables involved in the gas exchange process.
NASA Discipline Environmental Health↗
Ventilation-perfusion matching during exercise
In normal subjects, exercise widens the alveolar-arterial PO2 difference (P[A-a]O2) despite a more uniform topographic distribution of ventilation-perfusion (VA/Q) ratios. While part of the increase in P(A-a)O2 (especially during heavy exercise) is due to diffusion limitation, a considerable amount is caused by an increase in VA/Q mismatch as detected by the multiple inert gas elimination technique. Why this occurs is unknown, but circumstantial evidence suggests it may be related to interstitial pulmonary edema rather than to factors dependent on ventilation, airway gas mixing, airway muscle tone, or pulmonary vascular tone. In patients with lung disease, the gas exchange consequences of exercise are variable. Thus, arterial PO2 may increase, remain the same, or fall. In general, patients with advanced chronic obstructive pulmonary disease (COPD) or interstitial fibrosis who exercise show a fall in PO2. This is usually not due to worsening VA/Q relationships but mostly to the well-known fall in mixed venous PO2, which itself results from a relatively smaller increase in cardiac output than VO2. However, in interstitial fibrosis (but not COPD), there is good evidence that a part of the fall in PO2 on exercise is caused by alveolar-capillary diffusion limitation of O2 transport; in COPD (but not interstitial fibrosis), a frequent additional contributing factor to the hypoxemia of exercise is an inadequate ventilatory response, such that minute ventilation does not rise as much as does CO2 production or O2 uptake, causing arterial PCO2 to increase and PO2 to fall.
Non-NASA Center↗
Prolonged lobar hypoxia in vivo enhances the responsivity of isolated pulmonary veins to hypoxia
The hypoxic response of pulmonary vessels isolated from eight sheep whose right apical lobes (RAL) had inspired 100% N2 for 20 h was studied. The RAL of these conscious sheep inspired hypoxic gas and the remainder of the lung inspired air. During hypoxia, RAL perfusion was 33 +/- 3% of its air value, carotid arterial PO2 averaged 86 +/- 3 mm Hg and pulmonary perfusion pressure was not significantly different from the initial control period when the RAL inspired air. At the end of the hypoxic exposure, the sheep were killed, and pulmonary artery and vein rings (0.5 to 2 mm inner diameter) were isolated from both the RAL and the right cardiac lobe, which served as the control lobe (CL). Arteries from the RAL and CL did not contract in response to 6% O2/6% CO2/88% N2 (hypoxia). In contrast, RAL veins did contract vigorously in response to hypoxia, whereas CL veins did not contract or contracted only minimally. Rubbing of the endothelium or prior incubation of RAL veins with catalase (1,200 units/ml), indomethacin (10(-5) M), or the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist, SQ 29,548 (3 X 10(-6) M) each significantly reduced the response to hypoxia. RAL veins were also found to be more reactive than CL veins to the prostaglandin endoperoxide analogue U46619. We conclude that prolonged lobar hypoxia in vivo increases the responsivity of isolated pulmonary veins to hypoxia. These contractions may result from an increase in reactive O2 species, which in turn modify production of, metabolism of, and/or tissue responsivity to TxA2/PGH2.
NASA Discipline Cardiopulmonary↗
Automated Label‐Free Assay for Viral Detection and Inhibitor Screening via Biomembrane‐Functionalized Microelectrode Arrays
Most virus infection assays have indirect readout such as virus number following entry (e.g., PCR, cell lysis). While effective, these technologies are labor‐intensive, require specialized environments (e.g., sterile or RNA‐free), and detect later‐stage viral events like lysis or cell death, lacking sensitivity to early fusion events. To address these limitations, we present biologically relevant 2D membrane materials, host‐cell‐derived supported lipid bilayers (hcd‐SLBs), integrated with organic microelectrode arrays (OMEAs) for detection of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) fusion. By overexpressing angiotensin‐converting enzyme 2 (ACE2) receptors on the native membranes, the platform functions as a viral sensor capable of detecting virus pseudo particles (VPPs) through the late pathway. Additionally, hcd‐SLBs extracted from human lung epithelium expressing native ACE2 detect fusion events through the early pathway. The platform's utility as a drug‐screening tool is demonstrated by testing antibodies targeting either the ACE2 on the host membrane or the viral spike (S) proteins. To enhance the throughput, microfluidics are integrated for automation and OMEAs are incorporated within each channel, miniaturizing the testing units. This system supports high‐throughput data generation, automation, and scalability, providing an efficient platform for viral fusion detection that advances the study of pathogen‐host interactions and accelerates antiviral drug discovery.
Biology↗
Harnessing Particle Size‐Control and DNA‐Oligo Functionalization in ZIF‐76 for Biological Applications
Abstract Advanced therapeutics require novel nanocarriers to ensure their functionality is preserved during transit. Zeolitic imidazolate frameworks (ZIFs) have emerged as promising materials in this field owing to their combined biocompatibility, high porosity, and tunable chemistry. While a diverse family of ZIFs has been reported, few have been explored beyond the prototypical ZIF‐8. Herein, the size‐controlled synthesis of three distinct ZIF‐76 analogs is demonstrated, overcoming the unique synthetic challenges intrinsic to the lta topology and complex crystallization kinetics associated with the mixed linker approach. This assesses the materials’ platform effectiveness for intracellular delivery first by exploring the structural and colloidal stability in biologically relevant media. To circumvent particle aggregation, fluorescently labeled DNA oligonucleotides are post‐synthetically attached to the ZIF surface. This modification significantly improves the colloidal stability in media and facilitates particle internalization tracking. Finally, the particle‐cell interactions are assessed, revealing rapid cell membrane association with macrophages, but not lung epithelial cells, and ZIF accumulation within macrophages which increased over time. Importantly, this study outlines a generalized approach toward expanding the available library of ZIFs for biological applications, enabling the potential for targeted therapeutic delivery for intracellular infections treatment.
Deneff, Jacob I.↗
Codelivery of Paclitaxel and Parthenolide in Discoidal Bicelles for a Synergistic Anticancer Effect: Structure Matters
Nanotechnology has long been used to improve the tumor targeting of chemotherapeutics. The structure of these nanocarriers greatly affects their efficacy and toxicity. Herein, structurally stable nanodiscoidal phospholipid bicelles, which are capable of encapsulating anticancer drugs, paclitaxel (PTX) and parthenolide (PTL), are designed. This nanodiscoidal bicelle structure is shown previously to exhibit longer blood circulation, deeper tumor penetration, and increased tumor cell uptake compared with spherical particles of similar compositions. Structural characterization and loading capacity of the PTX‐ and PTL‐ loaded nanodiscs are conducted along with an investigation into the cytotoxicity of the bicelles based on the drug‐to‐lipid ratios of both drugs loaded separately and in combination. A significant synergistic effect between both loaded drugs is also observed in A549 lung cancer and drug‐resistant MDA‐MB‐231 cell lines. An in vivo study using mice bearing subcutaneous A549 tumors shows a long circulation time of the intravenously injected DiR‐loaded bicelles and significant antitumor efficacy of the PTX‐ and PTL‐loaded bicelles. This efficacious self‐assembled nanoparticle system displays great potential as a nanoplatform to codeliver multiple therapeutics or diagnostics for improving cancer therapy.
Rad, Armin Tahmasbi↗
Structure–Activity Relationships of Inactive‐Conformation Binding EGFR Inhibitors: Linking the ATP and Allosteric Pockets
ABSTRACT The epidermal growth factor receptor (EGFR) tyrosine kinase is an important therapeutic target in non‐small cell lung cancer (NSCLC). However, the continual emergence of resistance mutations in the treatment of EGFR mutation‐positive NSCLC with currently approved tyrosine kinase inhibitors warrants the development of next‐generation inhibitors. Since research for ATP‐competitive EGFR tyrosine kinase inhibitors (TKIs) that extend into the back pocket has been neglected in the recent past, we survey the extent to which such binding functional groups can be incorporated into an ATP‐site imidazole scaffold. We find thatmeta‐substituted amide linkers derivatized with fluorine in 2,6‐positions and/or a hydroxy group in 3‐position of the back pocket phenyl exhibit the highest potency. Structural insights into how the back pocket groups are bound through points of connection provide new directions for the discovery and optimization of inactive conformation targeting agents in EGFR and other kinases.
Chemistry↗
Feature‐shared adaptive‐boost deep learning for invasiveness classification of pulmonary subsolid nodules in CT images
Purpose In clinical practice, invasiveness is an important reference indicator for differentiating the malignant degree of subsolid pulmonary nodules. These nodules can be classified as atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), or invasive adenocarcinoma (IAC). The automatic determination of a nodule's invasiveness based on chest CT scans can guide treatment planning. However, it is challenging, owing to the insufficiency of training data and their interclass similarity and intraclass variation. To address these challenges, we propose a two‐stage deep learning strategy for this task: prior‐feature learning followed by adaptive‐boost deep learning. Methods The adaptive‐boost deep learning is proposed to train a strong classifier for invasiveness classification of subsolid nodules in chest CT images, using multiple 3D convolutional neural network (CNN)‐based weak classifiers. Because ensembles of multiple deep 3D CNN models have a huge number of parameters and require large computing resources along with more training and testing time, the prior‐feature learning is proposed to reduce the computations by sharing the CNN layers between all weak classifiers. Using this strategy, all weak classifiers can be integrated into a single network. Results Tenfold cross validation of binary classification was conducted on a total of 1357 nodules, including 765 noninvasive (AAH and AIS) and 592 invasive nodules (MIA and IAC). Ablation experimental results indicated that the proposed binary classifier achieved an accuracy of with an AUC of 81.3 . These results are superior compared to those achieved by three experienced chest imaging specialists who achieved an accuracy of , , and , respectively. About 200 additional nodules were also collected. These nodules covered 50 cases for each category (AAH, AIS, MIA, and IAC, respectively). Both binary and multiple classifications were performed on these data and the results demonstrated that the proposed method definitely achieves better performance than the performance achieved by nonensemble deep learning methods. Conclusions It can be concluded that the proposed adaptive‐boost deep learning can significantly improve the performance of invasiveness classification of pulmonary subsolid nodules in CT images, while the prior‐feature learning can significantly reduce the total size of deep models. The promising results on clinical data show that the trained models can be used as an effective lung cancer screening tool in hospitals. Moreover, the proposed strategy can be easily extended to other similar classification tasks in 3D medical images.
Wang, Jun↗
A bespoke health risk assessment methodology for the radiation protection of astronauts
An alternative approach that is particularly suitable for the radiation health risk assessment (HRA) of astronauts is presented. The quantity, Radiation Attributed Decrease of Survival (RADS), representing the cumulative decrease in the unknown survival curve at a certain attained age, due to the radiation exposure at an earlier age, forms the basis for this alternative approach. Results are provided for all solid cancer plus leukemia incidence RADS from estimated doses from theoretical radiation exposures accumulated during long-term missions to the Moon or Mars. For example, it is shown that a 1000-day Mars exploration mission with a hypothetical mission effective dose of 1.07 Sv at typical astronaut ages around 40 years old, will result in the probability of surviving free of all types of solid cancer and leukemia until retirement age (65 years) being reduced by 4.2% (95% CI 3.2; 5.3) for males and 5.8% (95% CI 4.8; 7.0) for females. RADS dose–responses are given, for the outcomes for incidence of all solid cancer, leukemia, lung and female breast cancer. Results showing how RADS varies with age at exposure, attained age and other factors are also presented. The advantages of this alternative approach, over currently applied methodologies for the long-term radiation protection of astronauts after mission exposures, are presented with example calculations applicable to European astronaut occupational HRA. Some tentative suggestions for new types of occupational risk limits for space missions are given while acknowledging that the setting of astronaut radiation-related risk limits will ultimately be decided by the Space Agencies. Suggestions are provided for further work which builds on and extends this new HRA approach, e.g., by eventually including non-cancer effects and detailed space dosimetry.
61 RADIATION PROTECTION AND DOSIMETRY↗
Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD
Pseudomonas aeruginosa is an increasingly antibiotic-resistant pathogen that causes severe lung infections, burn wound infections, and diabetic foot infections. P. aeruginosaproduces the siderophore pyochelin through the use of a non-ribosomal peptide synthetase (NRPS) biosynthetic pathway. Targeting members of siderophore NRPS proteins is one avenue currently under investigation for the development of new antibiotics against antibiotic-resistant organisms. Here, the crystal structure of the pyochelin adenylation domain PchD is reported. The structure was solved to 2.11 Å when co-crystallized with the adenylation inhibitor 5'-O-(N-salicylsulfamoyl)adenosine (salicyl-AMS) and to 1.69 Å with a modified version of salicyl-AMS designed to target an active site cysteine (4-cyano-salicyl-AMS). In the structures, PchD adopts the adenylation conformation, similar to that reported for AB3403 from Acinetobacter baumannii.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Modeling airborne pathogen transport and transmission risks of SARS-CoV-2
An integrated modeling approach has been developed to better understand the relative impacts of different expiratory and environmental factors on airborne pathogen transport and transmission, motivated by the recent COVID-19 pandemic. Computational fluid dynamics (CFD) modeling was used to simulate spatial-temporal aerosol concentrations and quantified risks of exposure as a function of separation distance, exposure duration, environmental conditions (e.g., airflow/ventilation), and face coverings. The CFD results were combined with infectivity models to determine probability of infection, which is a function of the spatial-temporal aerosol concentrations, viral load, infectivity rate, viral viability, lung-deposition probability, and inhalation rate. Uncertainty distributions were determined for these parameters from the literature. Probabilistic analyses were performed to determine cumulative distributions of infection probabilities and to determine the most important parameters impacting transmission. This modeling approach has relevance to both pathogen and pollutant dispersion from expelled aerosol plumes.
60 APPLIED LIFE SCIENCES↗