Engineering Papers⌕ Search

SEARCH · Engineering Papers

Results for “respiratory complex I”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Peptide-mimetic treatment of Pseudomonas aeruginosa in a mouse model of respiratory infection

The rise of drug resistance has become a global crisis, with >1 million deaths due to resistant bacterial infections each year. Pseudomonas aeruginosa, in particular, remains a serious problem with limited solutions due to complex resistance mechanisms that now lead to more than 32,000 multidrug-resistant (MDR) infections and over 2000 deaths in the U.S. annually. While the emergence of resistant bacteria has become ominously common, identification of useful new drug classes has been limited over the past over 40 years. We found that a potential novel therapeutic, the peptide-mimetic TM5, is effective at killing P. aeruginosa and displays sufficiently low toxicity in mammalian cells to allow for use in treatment of infections. Interestingly, TM5 kills P. aeruginosa more rapidly than traditional antibiotics, within 30–60 min in vitro, and is effective against a range of clinical isolates, including extensively drug resistant strains. In vivo, TM5 significantly reduced bacterial load in the lungs within 24 h compared to untreated mice and demonstrated few adverse effects. Taken together, these observations suggest that TM5 shows promise as an alternative therapy for MDR P. aeruginosa respiratory infections.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2010

DigitalHuman (DH): An Integrative Mathematical Model ofHuman Physiology

Mathematical models and simulation are important tools in discovering the key causal relationships governing physiological processes and improving medical intervention when physiological complexity is a central issue. We have developed a model of integrative human physiology called DigitalHuman (DH) consisting of -5000 variables modeling human physiology describing cardiovascular, renal, respiratory, endocrine, neural and metabolic physiology. Users can view time-dependent solutions and interactively introduce perturbations by altering numerical parameters to investigate new hypotheses. The variables, parameters and quantitative relationships as well as all other model details are described in XML text files. All aspects of the model, including the mathematical equations describing the physiological processes are written in XML open source, text-readable files. Model structure is based upon empirical data of physiological responses documented within the peer-reviewed literature. The model can be used to understand proposed physiological mechanisms and physiological interactions that may not be otherwise intUitively evident. Some of the current uses of this model include the analyses of renal control of blood pressure, the central role of the liver in creating and maintaining insulin resistance, and the mechanisms causing orthostatic hypotension in astronauts. Additionally the open source aspect of the modeling environment allows any investigator to add detailed descriptions of human physiology to test new concepts. The model accurately predicts both qualitative and more importantly quantitative changes in clinically and experimentally observed responses. DigitalHuman provides scientists a modeling environment to understand the complex interactions of integrative physiology. This research was supported by.NIH HL 51971, NSF EPSCoR, and NASA

Hester, Robert L.↗
DOE OSTI2021

Molecular understanding of heteronuclear active sites in heme–copper oxidases, nitric oxide reductases, and sulfite reductases through biomimetic modelling

Heme-copper oxidases (HCO), nitric oxide reductases (NOR), and sulfite reductases (SiR) catalyze the multi-electron and multi-proton reductions of O 2 , NO, and SO 3 2- , respectively. Each of these reactions is important to drive cellular energy production through respiratory metabolism and HCO, NOR, and SiR evolved to contain heteronuclear active sites containing heme/copper, heme/nonheme iron, and heme-[4Fe-4S] centers, respectively. The complexity of the structures and reactions of these native enzymes, along with their large sizes and/or membrane associations, make it challenging to fully understand the crucial structural features responsible for the catalytic properties of these active sites. Here, we summarize progress that has been made to better understand these heteronuclear metalloenzymes at the molecular level though study of the native enzymes along with insights gained from biomimetic models comprising either small molecules or proteins. Further understanding the reaction selectivity of these enzymes is discussed through comparisons of their similar heteronuclear active sites, and we offer outlook for further investigations and areas of ongoing study.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Plant-specific features of respiratory supercomplex I + III2 from Vigna radiata

Abstract The last steps of cellular respiration—an essential metabolic process in plants—are carried out by mitochondrial oxidative phosphorylation. This process involves a chain of multi-subunit membrane protein complexes (complexes I–V) that form higher-order assemblies called supercomplexes. Although supercomplexes are the most physiologically relevant form of the oxidative phosphorylation complexes, their functions and structures remain mostly unknown. Here we present the cryogenic electron microscopy structure of the supercomplex I + III 2 from Vigna radiata (mung bean). The structure contains the full subunit complement of complex I, including a newly assigned, plant-specific subunit. It also shows differences in the mitochondrial processing peptidase domain of complex III 2 relative to a previously determined supercomplex with complex IV. The supercomplex interface, while reminiscent of that in other organisms, is plant specific, with a major interface involving complex III 2 ’s mitochondrial processing peptidase domain and no participation of complex I’s bridge domain. The complex I structure suggests that the bridge domain sets the angle between the enzyme’s two arms, limiting large-scale conformational changes. Moreover, complex I’s catalytic loops and its response in active-to-deactive assays suggest that, in V. radiata , the resting complex adopts a non-canonical state and can sample deactive- or open-like conformations even in the presence of substrate. This study widens our understanding of the possible conformations and behaviour of complex I and supercomplex I + III 2 . Further studies of complex I and its supercomplexes in diverse organisms are needed to determine the universal and clade-specific mechanisms of respiration.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Improved deep learning prediction of antigen–antibody interactions

Identifying antibodies that neutralize specific antigens is crucial for developing effective immunotherapies, but this task remains challenging for many target antigens. The rise of deep learning–based computational approaches presents a promising avenue to address this challenge. Here, we assess the performance of a deep learning approach through two benchmark tests aimed at predicting antibodies for the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Three different strategies for constructing input sequence alignments are employed for predicting structural models of antigen–antibody complexes. In our initial testing set, which comprises known experimental structures, these strategies collectively yield a significant top-ranked prediction for 61% of cases and a success rate of 47%. Notably, one strategy that utilizes the sequences of known antigen binders outperforms the other two, achieving a precision of 90% in a subsequent test set of ~1,000 antibodies, balanced between true and control antibodies for the antigen, albeit with a lower recall of 25%. Our results underscore the potential of integrating deep learning methods with single B cell sequencing techniques to enhance the prediction accuracy of antigen–antibody interactions.

Science & Technology - Other Topics↗
NASA NTRS1995

Heart rate and respiratory rhythm dynamics on ascent to high altitude

OBJECTIVE--To investigate the alterations in autonomic control of heart rate at high altitude and to test the hypothesis that hypoxaemic stress during exposure to high altitude induces non-linear, periodic heart rate oscillations, similar to those seen in heart failure and the sleep apnoea syndrome. SUBJECTS--11 healthy subjects aged 24-64. MAIN OUTCOME MEASURES--24 hour ambulatory electrocardiogram records obtained at baseline (1524 m) and at 4700 m. Simultaneous heart rate and respiratory dynamics during 2.5 hours of sleep by fast Fourier transform analysis of beat to beat heart rate and of an electrocardiographically derived respiration signal. RESULTS--All subjects had resting hypoxaemia at high altitude, with an average oxyhaemoglobin saturation of 81% (5%). There was no significant change in mean heart rate, but low frequency (0.01-0.05 Hz) spectral power was increased (P < 0.01) at high altitude. Time series analysis showed a complex range of non-linear sinus rhythm dynamics. Striking low frequency (0.04-0.06 Hz) heart rate oscillations were observed during sleep in eight subjects at high altitude. Analysis of the electrocardiographically derived respiration signal indicated that these heart rate oscillations correlated with low frequency respiratory oscillations. CONCLUSIONS--These data suggest (a) that increased low frequency power during high altitude exposure is not simply attributable to increased sympathetic modulation of heart rate, but relates to distinctive cardiopulmonary oscillations at approximately 0.05 Hz and (b) that the emergence of periodic heart rate oscillations at high altitude is consistent with an unstable cardiopulmonary control system that may develop on acute exposure to hypoxaemic stress.

Non-NASA Center↗
NASA NTRS2001

Influence of respiratory motor neurone activity on human autonomic and haemodynamic rhythms

Although humans hold great advantages over other species as subjects for biomedical research, they also bring major disadvantages. One is that among the many rhythmic physiological signals that can be recorded, there is no sure way to know which individual change precedes another, or which change represents cause and which represents effect. In an attempt to deal with the inherent complexity of research conducted in intact human subjects, we developed and used a structural equation model to analyse responses of healthy young men to pharmacological changes of arterial pressure and graded inspiratory resistance, before and after vagomimetic atropine. Our model yielded a good fit of the experimental data, with a system weighted R2 of 0.77, and suggested that our treatments exerted both direct and indirect influences on the variables we measured. Thus, infusions of nitroprusside and phenylephrine exerted all of their direct effects by lowering and raising arterial pressure; the changes of R-R intervals, respiratory sinus arrhythmia and arterial pressure fluctuations that these drugs provoked, were indirect consequences of arterial pressure changes. The only direct effect of increased inspiratory resistance was augmentation of arterial pressure fluctuations. These results may provide a new way to disentangle and understand responses of intact human subjects to experimental forcings. The principal new insight we derived from our modelling is that respiratory gating of vagal-cardiac motor neurone firing is nearly maximal at usual levels of arterial pressure and inspiratory motor neurone activity.

Non-NASA Center↗
DOE OSTI2023

Monomer and dimer structures of cytochrome bo 3 ubiquinol oxidase from Escherichia coli

Abstract The Escherichia coli cytochrome bo 3 ubiquinol oxidase is a four‐subunit heme‐copper oxidase that serves as a proton pump in the E. coli aerobic respiratory chain. Despite many mechanistic studies, it is unclear whether this ubiquinol oxidase functions as a monomer, or as a dimer in a manner similar to its eukaryotic counterparts—the mitochondrial electron transport complexes. In this study, we determined the monomeric and dimeric structures of the E. coli cytochrome bo 3 ubiquinol oxidase reconstituted in amphipol by cryogenic electron microscopy single particle reconstruction (cryo‐EM SPR) to a resolution of 3.15 and 3.46 Å, respectively. We have discovered that the protein can form a dimer with C2 symmetry, with the dimerization interface maintained by interactions between the subunit II of one monomer and the subunit IV of the other monomer. Moreover, the dimerization does not induce significant structural changes in the monomers, except the movement of a loop in subunit IV (residues 67–74).

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1974

Studies on disease transmission in spacecraft environments

The effects of the Skylab gas mixtures on general health and immunocompetence of mice and ferrets subjected to the Skylab space cabin environment (SCE) were initially studied in a stainless steel low pressure facility which was maintained at gas ratios of 30% nitrogen and 70% oxygen under 5 psia, and which consisted of two subchambers, that permitted mutual isolation of experimental groups and/or selective removal of animals without return of the entire cabin to ambient pressure was developed. The studies demonstrated that ferrets immunized with Brucella Strain 19 prior to being housed in SCE had decreased synthesis of IgG compared to their respective controls. The possibility of latent infections being responsible for stress-induced upper respiratory diseases of astronauts required that the role of neutralizing antibody as a function of antibody affinity/avidity be investigated. The model consisted of Aleutian disease virus (ADV) which infects ferrets and mink resulting in nonneutralized immune complexes. These studies demonstrated that early antibody to ADV had lower affinity/avidity than late antibody with respect to chronicity. These studies culminated in a description of antibody affinity, first isolation of ADV and its cultivation in vitro.

Kenyon, A. J.↗
DOE OSTI2020

Deducing the N- and O-glycosylation profile of the spike protein of novel coronavirus SARS-CoV-2

The current emergence of the novel coronavirus pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demands the development of new therapeutic strategies to prevent rapid progress of mortalities. The coronavirus spike (S) protein, which facilitates viral attachment, entry and membrane fusion is heavily glycosylated and plays a critical role in the elicitation of the host immune response. The spike protein is comprised of two protein subunits (S1 and S2), which together possess 22 potential N-glycosylation sites. Herein, we report the glycosylation mapping on spike protein subunits S1 and S2 expressed on human cells through high-resolution mass spectrometry. We have characterized the quantitative N-glycosylation profile on spike protein and interestingly, observed unexpected O-glycosylation modifications on the receptor-binding domain of spike protein subunit S1. Even though O-glycosylation has been predicted on the spike protein of SARS-CoV-2, this is the first report of experimental data for both the site of O-glycosylation and identity of the O-glycans attached on the subunit S1. Our data on the N- and O-glycosylation are strengthened by extensive manual interpretation of each glycopeptide spectra in addition to using bioinformatics tools to confirm the complexity of glycosylation in the spike protein. Here, the elucidation of the glycan repertoire on the spike protein provides insights into the viral binding studies and more importantly, propels research toward the development of a suitable vaccine candidate.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Cross-protective antibodies against common endemic respiratory viruses

Respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and human parainfluenza virus types one (HPIV1) and three (HPIV3) can cause severe disease and death in immunocompromised patients, the elderly, and those with underlying lung disease. A protective monoclonal antibody exists for RSV, but clinical use is limited to high-risk infant populations. Hence, therapeutic options for these viruses in vulnerable patient populations are currently limited. Here, we present the discovery, in vitro characterization, and in vivo efficacy testing of two cross-neutralizing monoclonal antibodies, one targeting both HPIV3 and HPIV1 and the other targeting both RSV and HMPV. The 3 × 1 antibody is capable of targeting multiple parainfluenza viruses; the MxR antibody shares features with other previously reported monoclonal antibodies that are capable of neutralizing both RSV and HMPV. We obtained structures using cryo-electron microscopy of these antibodies in complex with their antigens at 3.62 Å resolution for 3 × 1 bound to HPIV3 and at 2.24 Å for MxR bound to RSV, providing a structural basis for in vitro binding and neutralization. Together, a cocktail of 3 × 1 and MxR could have clinical utility in providing broad protection against four of the respiratory viruses that cause significant morbidity and mortality in at-risk individuals.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Structure-Based Design and Antigenic Validation of Respiratory Syncytial Virus G Immunogens

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease of children, the elderly, and immunocompromised individuals. Currently, there are no FDA-approved RSV vaccines. The RSV G glycoprotein is used for viral attachment to host cells and impairment of host immunity by interacting with the human chemokine receptor CX3CR1. Antibodies that disrupt this interaction are protective against infection and disease. Nevertheless, development of an RSV G vaccine antigen has been hindered by its low immunogenicity and safety concerns. A previous study described three engineered RSV G proteins containing single-point mutations that induce higher levels of IgG antibodies and have improved safety profiles compared to wild-type RSV G. However, it is unclear if the mutations affect RSV G protein folding and display of its conformational epitopes. In this study, we show that the RSV G S177Q protein retains high-affinity binding to protective human and mouse monoclonal antibodies and has equal reactivity as wild-type RSV G protein to human reference immunoglobulin to RSV. Additionally, we determined the high-resolution crystal structure of RSV G S177Q protein in complex with the anti-RSV G antibody 3G12, further validating its antigenic structure. These studies show for the first time that an engineered RSV G protein with increased immunogenicity and safety retains conformational epitopes to high-affinity protective antibodies, supporting its further development as an RSV vaccine immunogen. Respiratory syncytial virus (RSV) causes severe lower respiratory diseases of children, the elderly, and immunocompromised populations. There currently are no FDA-approved RSV vaccines. Most vaccine development efforts have focused on the RSV F protein, and the field has generally overlooked the receptor-binding antigen RSV G due to its poor immunogenicity and safety concerns. However, single-point mutant RSV G proteins have been previously identified that have increased immunogenicity and safety. In this study, we investigate the antibody reactivities of three known RSV G mutant proteins. We show that one mutant RSV G protein retains high-affinity binding to protective monoclonal antibodies, is equally recognized by anti-RSV antibodies in human sera, and forms the same three-dimensional structure as the wild-type RSV G protein. Our study validates the structure-guided design of the RSV G protein as an RSV vaccine antigen.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2008

Validation of On-Orbit Methodology for the Assessment of Cardiac Function and Changes in the Circulating Volume Using Ultrasound and "Braslet-M" Occlusion Cuffs

Recent advances in remotely guided imaging techniques on ISS allow the acquisition of high quality ultrasound data using crewmember operators with no medical background and minimal training. However, ongoing efforts are required to develop and validate methodology for complex imaging protocols to ensure their repeatability, efficiency, and suitability for use aboard the ISS. This Station Developmental Test Objective (SDTO) tests a cardiovascular evaluation methodology that takes advantage of the ISS Ultrasound capability, the Braslet-M device, and modified respiratory maneuvers (Valsalva and Mueller), to broaden the spectrum of anatomical and functional information on human cardiovascular system during long-duration space missions. The proposed methodology optimizes and combines new and previously demonstrated methods, and is expected to benefit medically indicated assessments, operational research protocols, and data collections for science. Braslet-M is a current Russian operational countermeasure that compresses the upper thigh to impede the venous return from lower extremities. The goal of the SDTO is to establish and validate a repeatable ultrasound-based methodology for the assessment of a number of cardiovascular criteria in microgravity. Braslet-M device is used as a means to acutely alter volume distribution while focused ultrasound measurements are performed. Modified respiratory maneuvers are done upon volume manipulations to record commensurate changes in anatomical and functional parameters. The overall cardiovascular effects of the Braslet-M device are not completely understood, and although not a primary objective of this SDTO, this effort will provide pilot data regarding the suitability of Braslet-M for its intended purpose, effects, and the indications for its use.

Bogomolov, V. V.↗
DOE OSTI2022

Mitochondrial respiratory chain protein co-regulation in the human brain

Mitochondrial respiratory chain (RC) function requires the stoichiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimer's disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2–4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Atmospheric Composition and Radiative Forcing Effects due to UN International Ship Emissions Regulations (ACRUISE) Field Campaign Report

Aerosols, or atmospheric particulates, are long known to be able to seed clouds and modify their characteristics (e.g., cloud brightness, coverage, lifetime). However, the impact of aerosols on clouds is highly complex and non-linear. As a result, aerosol-cloud interaction remains the largest uncertainty in our understanding of the Earth’s radiative balance and in any future climate projections. Aerosols are also a principal component of air pollution and are known to adversely affect respiratory and cardiovascular health.

54 ENVIRONMENTAL SCIENCES↗
NASA NTRS2001

Three-dimensional ballistocardiography and respiratory motion in sustained microgravity

BACKGROUND: We measured the three-dimensional ballistocardiogram (BCG) in a free-floating subject in sustained microgravity during spaceflight to test the usefulness of such measurements for future non-invasive monitoring of cardiac function, and to examine the effects of respiratory movement on the BCG in three axes. METHODS: Acceleration was measured using a three-axis accelerometer fastened to the lumbar region of the subject while simultaneous recordings of ECG, and respiratory motion via impedance plethysmography were also made. Data were recorded during a 146-s period of inactivity on the part of the subject during which time there was no contact with the spacecraft. RESULTS: Total body motion due to respiratory activity was consistent with that calculated from the known action of the diaphragm and conservation of momentum. The accelerations due to cardiac activity, ensemble averaged over the R-R interval, were greatest along the head-to-foot axis. Maximum amplitude of the HIJK complex of the BCG generated by ventricular ejection was greatest in the head to foot axis (approximately 70 x 10(-3) m x s(-2)), but there were also substantial accelerations along the dorsoventral axis of up to 43 10(-3) m x s(-2), that are not measured interrestrial two-dimensional studies. The amplitude of the BCG was strongly affected by lung volume, with accelerations being reduced 50 to 70% between end-inspiration and end-expiration. CONCLUSIONS: These data suggest a greatly reduced transmission of the cardiac motion to the body at end-expiration (FRC) than at higher lung volumes. The BCG might be further developed as a non-invasive means of monitoring parameters such as stroke volume in microgravity.

Flight Experiment↗
NASA NTRS1979

Energy transduction in Halobacterium halobium

The properties and functions of the light-energy-transducing purple membrane of Halobacterium halobium are reviewed. Consideration is given to the protein structure and composition of the membrane and the photochemistry of the protein-retinal complex known as bacteriorhodopsin. The role of bacteriorhodpsin in establishing and maintaining an electrochemical (H(+)) gradient is examined, and interactions of this gradient with Na(+) and K(+) gradients, the light-induced transport of amino acids and the light-induced phosphorylation of ADP are considered. Bacteriorhodopsin and the respiratory chain are discussed as alternative sources of energy for the maintenance of the H(+) gradient. Advantages of the Halobacterium purple membrane system for studies of membrane energetics and the confirmation of the chemiosmotic hypothesis are also noted.

Lanyi, J. K.↗