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At least 145 records · Page 8

Global Premature Mortality Due to Anthropogenic Outdoor Air Pollution and the Contribution of Past Climate Change

Increased concentrations of ozone and fine particulate matter (PM2.5) since preindustrial times reflect increased emissions, but also contributions of past climate change. Here we use modeled concentrations from an ensemble of chemistry–climate models to estimate the global burden of anthropogenic outdoor air pollution on present-day premature human mortality, and the component of that burden attributable to past climate change. Using simulated concentrations for 2000 and 1850 and concentration–response functions (CRFs), we estimate that, at present, 470 000 (95% confidence interval, 140 000 to 900 000) premature respiratory deaths are associated globally and annually with anthropogenic ozone, and 2.1 (1.3 to 3.0) million deaths with anthropogenic PM2.5-related cardiopulmonary diseases (93%) and lung cancer (7%). These estimates are smaller than ones from previous studies because we use modeled 1850 air pollution rather than a counterfactual low concentration, and because of different emissions. Uncertainty in CRFs contributes more to overall uncertainty than the spread of model results. Mortality attributed to the effects of past climate change on air quality is considerably smaller than the global burden: 1500 (−20 000 to 27 000) deaths yr (exp -1) due to ozone and 2200 (−350 000 to 140 000) due to PM2.5. The small multi-model means are coincidental, as there are larger ranges of results for individual models, reflected in the large uncertainties, with some models suggesting that past climate change has reduced air pollution mortality.

human health↗

Linear operating region in the ozone dial photon counting system

Ozone is a relatively unstable molecule found in Earth's atmosphere. An ozone molecule is made up of three atoms of oxygen. Depending on where ozone resides, it can protect or harm life on Earth. High in the atmosphere, about 15 miles up, ozone acts as a shield to protect Earth's surface from the sun's harmful ultraviolet radiation. Without this shield, we would be more susceptible to skin cancer, cataracts, and impaired immune systems. Closer to Earth, in the air we breathe, ozone is a harmful pollutant that causes damage to lung tissue and plants. Since the early 1980's, airborne lidar systems have been used for making measurements of ozone. The differential absorption lidar (DIAL) technique is used in the remote measurement of O3. This system allows the O3 to be measured as function of the range in the atmosphere. Two frequency-doubled Nd:YAG lasers are used to pump tunable dye lasers. The lasers are operating at 289 nm for the DIAL on-line wavelength of O3, and the other one is operated at 300 nm for the off-line wavelength. The DIAL wavelengths are produced in sequential laser pulses with a time separation of 300 micro s. The backscattered laser energy is collected by telescopes and measured using photon counting systems. The photon counting system measures the light signal by making use of the photon nature of light. The output pulse from the Photo-Multiplier Tube (PE), caused by a photon striking the PMT photo-cathode, is amplified and passed to a pulse height discriminator. The peak value of the pulse is compared to a reference voltage (discrimination level). If the pulse amplitude exceeds the discrimination level, the discriminator generates a standard pulse which is counted by the digital counter. Non-linearity in the system is caused by the overlapping of pulses and the finite response time of the electronics. At low count rates one expects the system to register one event for each output pulse from the PMT corresponding to a photon incident upon the photocathode, however, at higher rates the limitations of the discrimination/counting system will cause the observed count rate to be non-linear with respect to the true count rate. Depending on the pulse height distribution and the discriminator level, the overlapping of pulses (pulse pile-up) can cause count loss or even an additional apparent count gain as the signal levels increase. Characterization of the system, including the pulse height distribution, the signal to noise ratio, and the effect of the discriminator threshold level, is critical in maximizing the linear operating region of the system, thus greatly increasing the useful dynamic range of the system.

Andrawis, Madeleine↗

Structural Model Tuning Capability in an Object-Oriented Multidisciplinary Design, Analysis, and Optimization Tool

Updating the finite element model using measured data is a challenging problem in the area of structural dynamics. The model updating process requires not only satisfactory correlations between analytical and experimental results, but also the retention of dynamic properties of structures. Accurate rigid body dynamics are important for flight control system design and aeroelastic trim analysis. Minimizing the difference between analytical and experimental results is a type of optimization problem. In this research, a multidisciplinary design, analysis, and optimization [MDAO] tool is introduced to optimize the objective function and constraints such that the mass properties, the natural frequencies, and the mode shapes are matched to the target data as well as the mass matrix being orthogonalized.

Lung, Shun-fat↗

Structural Model Tuning Capability in an Object-Oriented Multidisciplinary Design, Analysis, and Optimization Tool

Updating the finite element model using measured data is a challenging problem in the area of structural dynamics. The model updating process requires not only satisfactory correlations between analytical and experimental results, but also the retention of dynamic properties of structures. Accurate rigid body dynamics are important for flight control system design and aeroelastic trim analysis. Minimizing the difference between analytical and experimental results is a type of optimization problem. In this research, a multidisciplinary design, analysis, and optimization (MDAO) tool is introduced to optimize the objective function and constraints such that the mass properties, the natural frequencies, and the mode shapes are matched to the target data as well as the mass matrix being orthogonalized.

Lung, Shun-fat↗

Threat Agnostic Virulence Assessment of Pathogens

Virulence assessment of new, emerging, and engineered pathogens is critical to mounting an appropriate response to a biothreat agent. The capacity of the pathogen to colonize human and harm tissues must be characterized to understand pathogenicity pathways and optimize diagnosis and treatment of resulting disease. Respiratory pathogens are of interest because they can have high transmissibility rates, as observed with the SARS-CoV-2 virus, the causative agent of Covid-19. Current technologies are insufficient to assess threats due to their reliance on systems with only one cell type and on sequencing the pathogen. However, it is known that sequence is not an accurate predictor of function, and sequencing can be unreliable for newly emerged or engineered pathogens. An ideal system would consist of relevant epithelial cell types and an assay sensitive enough to detect changes in host responses that do not rely on DNA sequencing. We chose a system consisting of host lung epithelial cells that can be used to assess the virulence of unknown respiratory pathogens. We interrogated pathogens using this model and assess features of pathogenicity. Our objective is to leverage PNNLs strengths in tissue engineering and proteomics capabilities to build a multiple reaction monitoring (MRM) or parallel reaction monitoring (PRM) liquid chromatography-tandem mass spectrometry assay for human host cell proteins whose abundance is influenced by infection. These responses can were then assessed for relative virulence using pathogen agnostic signatures. When confronted with a pathogen, cells activate dedicated signaling pathways, typically through phosphorylation of regulatory proteins and downstream activation of host cell networks.

59 BASIC BIOLOGICAL SCIENCES↗

Risk cross sections and their application to risk estimation in the galactic cosmic-ray environment

Radiation risk cross sections (i.e. risks per particle fluence) are discussed in the context of estimating the risk of radiation-induced cancer on long-term space flights from the galactic cosmic radiation outside the confines of the earth's magnetic field. Such quantities are useful for handling effects not seen after low-LET radiation. Since appropriate cross-section functions for cancer induction for each particle species are not yet available, the conventional quality factor is used as an approximation to obtain numerical results for risks of excess cancer mortality. Risks are obtained for seven of the most radiosensitive organs as determined by the ICRP [stomach, colon, lung, bone marrow (BFO), bladder, esophagus and breast], beneath 10 g/cm2 aluminum shielding at solar minimum. Spectra are obtained for excess relative risk for each cancer per LET interval by calculating the average fluence-LET spectrum for the organ and converting to risk by multiplying by a factor proportional to R gamma L Q(L) before integrating over L, the unrestricted LET. Here R gamma is the risk coefficient for low-LET radiation (excess relative mortality per Sv) for the particular organ in question. The total risks of excess cancer mortality obtained are 1.3 and 1.1% to female and male crew, respectively, for a 1-year exposure at solar minimum. Uncertainties in these values are estimated to range between factors of 4 and 15 and are dominated by the biological uncertainties in the risk coefficients for low-LET radiation and in the LET (or energy) dependence of the risk cross sections (as approximated by the quality factor). The direct substitution of appropriate risk cross sections will eventually circumvent entirely the need to calculate, measure or use absorbed dose, equivalent dose and quality factor for such a high-energy charged-particle environment.

NASA Discipline Radiation Health↗

Curvilinear Displacement Transfer Functions for Deformed Shape Predictions of Curved Structures Using Distributed Surface Strains

Curvilinear Displacement Transfer Functions were formulated for deformed shape predictions of different curved structures using surface strains. The embedded curved beam (depth-wise cross section of a curved structure along a surface strain-sensing line) was discretized into multiple small domains, with domain junctures matching the strain-sensing stations. Thus, the surface strain distribution can be described with a piecewise linear or a piecewise nonlinear function. The discrete approach enabled piecewise integrations of a curvature-strain differential equation for the embedded curved beam to yield closed-form Curvilinear Displacement Transfer Functions, which are written in terms of embedded curved-beam geometrical parameters and surface strains. By inputting the surface strain data, the Curvilinear Displacement Transfer Functions can transform surface strains into deflections along each embedded curved beam for mapping out the overall structural deformed shapes. The finite-element method was used to analytically generate the surface strains of the curved beams. The deformed shape prediction accuracies were then determined by comparing the theoretical deflections with the finite-element-generated deflections, which were used as yardsticks. By introducing the correction factors in simple mathematical forms, the Curvilinear Displacement Transfer Functions can be quite accurate for shape predictions of different curved-beam structures ranging from limit case of straight beam up to semicircular curved beam.

Ko, William L.↗

Hardware-in-Loop Modules for Testing Automated Ventilator Controllers

Automated ventilator controllers have the potential to simplify oxygen and carbon dioxide management for trauma. In the pre-hospital or military medicine environment, trauma care can be required for prolonged periods by personnel with limited ventilator management training. As such, there is a need for closed-loop control systems that can adapt ventilator management to a complex, ever-changing medical environment. Here, we present a novel hardware-in-loop test platform for the independent troubleshooting and evaluation of oxygen and carbon dioxide automated ventilator management capabilities. The oxygen management system provides an analogue blood oxygen signal that is responsive to the fraction of inspired oxygen and the peak inspiratory pressure ventilator settings. A tested oxygenation controller successfully reached the target oxygen saturation within 5 min. The carbon dioxide removal system integrates with commercial ventilator technology and mimics carbon dioxide generation, lung compliance, and airway resistance while providing an end-tidal carbon dioxide level that is responsive to changes in the tidal volume and respiratory rate settings. A test mechanical ventilator controller was able to regulate EtCO2 regardless of the starting value within 10 min. This highlights the system’s functionality and provides proof-of-concept demonstrations for how the hardware-in-loop test platforms can be used for evaluating closed-loop controller technologies.

Berard, David (ORCID:0000000322863846)↗

Effect of microgravity and hypergravity on deposition of 0.5- to 3-micron-diameter aerosol in the human lung

We measured intrapulmonary deposition of 0. 5-, 1-, 2-, and 3-micron-diameter particles in four subjects on the ground (1 G) and during parabolic flights both in microgravity (microG) and at approximately 1.6 G. Subjects breathed aerosols at a constant flow rate (0.4 l/s) and tidal volume (0.75 liter). At 1 G and approximately 1.6 G, deposition increased with increasing particle size. In microG, differences in deposition as a function of particle size were almost abolished. Deposition was a nearly linear function of the G level for 2- and 3-micron-diameter particles, whereas for 0.5- and 1.0-micron-diameter particles, deposition increased less between microG and 1 G than between 1 G and approximately 1.6 G. Comparison with numerical predictions showed good agreement for 1-, 2-, and 3-micron-diameter particles at 1 and approximately 1.6 G, whereas the model consistently underestimated deposition in microG. The higher deposition observed in microG compared with model predictions might be explained by a larger deposition by diffusion because of a higher alveolar concentration of aerosol in microG and to the nonreversibility of the flow, causing additional mixing of the aerosols.

Flight Experiment↗

A Solid-State Compressor for Integration of CO2 Removal and Reduction Assemblies

Integration of CO2 removal and reduction assemblies in a spacecraft air revitalization system requires an interface with the functionality of a vacuum pump/compressor and a buffer tank. The compressor must meet the vacuum needs of the CO2 removal unit and the pressure needs of the CO2 reduction device, and must also store sufficient CO2 to accommodate the differences in cycle times of the two processes. In this presentation, we describe the design and operation of an adsorption-based device sized for use on the International Space Station. The adsorption compressor functions at a power level approximately ten times lower than a comparable mechanical compression/buffer tank system. The unit is also smaller, lighter, and quieter than its mechanical counterpart.

Mulloth, Lila M.↗

Cardiopulmonary adaptation to weightlessness

The lung is profoundly affected by gravity. The absence of gravity (microgravity) removes the mechanical stresses acting on the lung paranchyma itself, resulting in a reduction in the deformation of the lung due to its own weight, and consequently altering the distribution of fresh gas ventilation within the lung. There are also changes in the mechanical forces acting on the rib cage and abdomen, which alters the manner in which the lung expands. The other way in which microgravity affects the lung is through the removal of the gravitationally induced hydrostatic gradients in vascular pressures, both within the lung itself, and within the entire body. The abolition of a pressure gradient within the pulmonary circulation would be expected to result in a greater degree of uniformity of blood flow within the lung, while the removal of the hydrostatic gradient within the body should result in an increase in venous return and intra-thoracic blood volume, with attendant changes in cardiac output, stroke volume, and pulmonary diffusing capacity. During the 9 day flight of Spacelab Life Sciences-1 (SLS-1) we collected pulmonary function test data on the crew of the mission. We compared the results obtained in microgravity with those obtained on the ground in both the standing and supine positions, preflight and in the week immediately following the mission. A number of the tests in the package were aimed at studying the anticipated changes in cardiopulmonary function, and we report those in this communication.

short duration↗

Studies of the effects of gravitational and inertial forces on cardiovascular and respiratory dynamics

The current status and application are described of the biplane video roentgen densitometry, videometry and video digitization systems. These techniques were developed, and continue to be developed for studies of the effects of gravitational and inertial forces on cardiovascular and respiratory dynamics in intact animals and man. Progress is reported in the field of lung dynamics and three-dimensional reconstruction of the dynamic thoracic contents from roentgen video images. It is anticipated that these data will provide added insight into the role of shape and internal spatial relationships (which is altered particularly by acceleration and position of the body) of these organs as an indication of their functional status.

Ritman, E. L.↗

The response of single human cells to zero gravity

The SO15 experiment was designed to extend observations of the effects of zero-gravity to living human cells during and subsequent to a 59-day flight on Skylab 3. A strain of diploid human embryonic lung cells, WI-38, was chosen for this purpose. The studies were concerned with observations designed to detect the effects of zero-gravity on cell growth rates and on cell structure as observed by light microscopy, transmission and scanning electron microscopy and histochemistry. Studies of the effects of zero-gravity on the cell function and the cell cycle were performed by time lapse motion picture photography and microspectrophotometry. Subsequent study of the returned living cells included karotyping, G- and C-banding, and analyses of the culture media used. Some of the living cells returned were banked by deep freeze techniques for possible future experiments.

Montgomery, P. O., Jr.↗

Pulmonary ACE2 expression in neonatal and adult rats

Children show a distinct presentation of COVID‐19, characterized by a lower incidence and mild phenotype, but the reason for this is still unknown. The angiotensin‐converting enzyme 2 (ACE2) functions as the primary cell entry receptor for Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and is thought to cause distinct clinical features between children and old people. The primary purpose of this study was to determine whether differences exist in the level of expression and distribution of ACE2 between neonatal and adult rat lungs. The lung tissues from rats of various ages were used to investigate the expression patterns of ACE2. Western blot, immunohistochemistry, and immunofluorescence were used to quantify or identify the localization of ACE2 in rat lungs. ACE2 was homogenously expressed in fewer alveolar type II (AT2) cells in the neonatal lung, with no polarization to the alveolar space and additional expression in pulmonary endothelium when compared to adult rat lungs. These findings suggest that the patterns of ACE2 distribution and cellular localization in rat lungs change with age.

Zhao, Depeng↗

Effect of water immersion on cardiopulmonary physiology at high gravity (+Gz)

The cardiopulmonary responses of eight male subject between 21-31 years exposed to 1, 2, and 3 Gz during immersion at 35 + or - 0.5 C to heart level and during control dry rides are studied. Ventilation, O2 consumption, the end-tidal pressure of CO2, heart frequency, cardiac output, functional residual capacity, and the arterial pressure of CO2 were measured. It is observed that as Gz increases ventilation, heart frequency, and O2 consumption increase, and the end-tidal and arterial pressures of CO2 decrease during dry rides, but are not altered during immersion. It is detected that the functional residual capacity is lower during immersion and decreases in both the dry and immersed state as Gz increases, and cardiac output decreases as Gz increases in dry rides. It is noted that changes produced by acceleration in a Gz direction are due to the effect on the systemic circulation rather than to the effect on the lungs.

Arieli, R.↗

Machine learning-assisted elucidation of CD81–CD44 interactions in promoting cancer stemness and extracellular vesicle integrity

Tumor-initiating cells with reprogramming plasticity or stem-progenitor cell properties (stemness) are thought to be essential for cancer development and metastatic regeneration in many cancers; however, elucidation of the underlying molecular network and pathways remains demanding. Combining machine learning and experimental investigation, here we report CD81, a tetraspanin transmembrane protein known to be enriched in extracellular vesicles (EVs), as a newly identified driver of breast cancer stemness and metastasis. Using protein structure modeling and interface prediction-guided mutagenesis, we demonstrate that membrane CD81 interacts with CD44 through their extracellular regions in promoting tumor cell cluster formation and lung metastasis of triple negative breast cancer (TNBC) in human and mouse models. In-depth global and phosphoproteomic analyses of tumor cells deficient with CD81 or CD44 unveils endocytosis-related pathway alterations, leading to further identification of a quality-keeping role of CD44 and CD81 in EV secretion as well as in EV-associated stemness-promoting function. CD81 is coexpressed along with CD44 in human circulating tumor cells (CTCs) and enriched in clustered CTCs that promote cancer stemness and metastasis, supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights machine learning as a powerful tool in facilitating the molecular understanding of new molecular targets in regulating stemness and metastasis of TNBC.

59 BASIC BIOLOGICAL SCIENCES↗

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↗