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Sex differences and deep space stressors: effects of 5-ion gcrsim, simulated microgravityand social isolation on immune function, brain, and behavior in mice

This project is testing the hypothesis that Ionizing Radiation (IR), microgravity and social isolation combine synergistically to trigger an oxidative stress response that alters immune homeostasis, brain structure/function, and neurobehavioral/cognitive performance. Specific Aims for this project are to: (1) Determine dose-response curves for acute ‘Five-Ion GCR Simulation’ exposure for immune, brain and performance responses in crew age-matched adult male and female mice; (2) Determine effects of acute ‘Five-Ion GCR Simulation’ exposure singly and in combination with simulated microgravity and social isolation, on immune, brain and performance responses in crew age-matched male and female mice mimicking deep space missions; and (3) Determine efficacy of the dietary antioxidant, Nicotinamide Mononucleotide (NMN), a key intermediate in nicotinamide adenine dinucleotide (NAD+) biosynthesis. Here we report findings from our studies of mature (24-week-old) male and female mice exposed to simulated 5-Ion GCRsim (0, 5, 15, or 50cGy) at the NASA Space Radiation Laboratory (NSRL) followed by combinatorial exposures to 15cGy, simulated microgravity via head-down tilt (hindlimb unloading) and social isolation. Immune, brain and behavioral (sensorimotor, risk-taking & cognitive) measures were acquired at ‘Acute’ (IR+24hrs, IR+72hrs), ‘Intermediate’ (IR+14 days) and ‘Delayed’ (IR+28 to IR+124 days) to inform biological responses anticipated during a transit to Mars. This project addresses NASA’s efforts to characterize risks and identify appropriate countermeasures in both women and men in anticipation of future deep space missions. Ensuring crew health and performance during extended transits necessitates that sensorimotor and cognitive abilities remain strong to avoid potentially catastrophic health and safety outcomes. Supported by the NASA Human Research Program (HRP) Human Factors Behavioral Performance Element Grant 18 18FLAG 2 0028.

behavioral sciences↗

DOE OSTI2023

Analysis of tumor-immune functional responses in a mathematical model of neoantigen cancer vaccines

Cancer neoantigen vaccines have emerged as a promising approach to stimulating the immune system to fight cancer. We propose a simple model including key elements of cancer-immune interactions and conduct a phase plane analysis to understand the immunological mechanisms of cancer neoantigen vaccines. Analytical results are obtained for two widely used functional forms that represent the killing rate of tumor cells by immune cells: the law of mass action (LMA) and the dePillis-Radunskaya Law (LPR). Using the LMA, our results reveal that a slowly growing tumor can escape the immune surveillance and that there is a unique periodic solution. The LPR offers richer dynamics, in which tumor elimination and uncontrolled tumor growth are both present. We show that tumor elimination requires sufficient number of initial activated T cells in relationship to the malignant cells, which lends support to using the neoantigen cancer vaccine as an adjuvant therapy after the primary tumor is surgically removed or treated using radiotherapy. We also derive a sufficient condition for uncontrolled tumor growth under the assumption of the LPR. Here, the juxtaposition of analyses with these two different choices for the killing rate function highlights their importance on model behavior and biological implications, by which we hope to spur further theoretical and experimental work to understand mechanisms underlying different functional forms for the killing rate.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

DYNC1H1 regulates NSCLC cell growth and metastasis by IFN-γ-JAK-STAT signaling and is associated with an aberrant immune response

Highlights: • DYNC1H1 is upregulated and its high expression predicted poor outcomes in NSCLC. • Loss of function of DYNC1H1 inhibits cell growth and metastasis of NSCLC cells in vitro. • DYNC1H1 knockdown inhibited metastasis of NSCLC cells in vivo. • DYNC1H1 loss of function suppresses IFN-γ-JAK-STAT signaling pathway in NSCLC. • DYNC1H1 expression is correlated with aberrant immune response in NSCLC indicated by analysis of TCGA immune data. It is urgent to identify new biomarkers and therapeutic targets to ameliorate the clinical prognosis of patients with lung cancer. The functional significance and molecular mechanism of dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) in nonsmall cell lung cancer (NSCLC) progression is still elusive. In our current study, publicly available data and Western blotting experiments confirmed that DYNC1H1 expression was upregulated in lung cancer samples compared with noncancerous samples. Quantitative real-time PCR (qPCR) results indicated that high DYNC1H1 expression in lung cancer tissues was significantly associated with clinical tumor stage and distal metastasis; moreover, its high expression was negatively correlated with prognosis. Functional experiments demonstrated that DYNC1H1 loss of function caused a significant decrease in cell viability and cell proliferative ability, inhibition of the cell cycle, and promotion of both migration potential and invasion potential in vitro. Animal experiments by tail vein injection of lung cancer cells showed that DYNC1H1 knockdown significantly decreased lung cancer metastasis. Mechanistically, the results from a human protein array showed changes in the IFN-γ-JAK-STAT signaling pathway, and analysis of The Cancer Genome Atlas (TCGA) immune data demonstrated that disturbance of the immune microenvironment might be involved in the impaired growth and metastatic ability mediated by DYNC1H1 loss in NSCLC. DYNC1H1 might serve as a promising biological marker of prognosis and a potential clinical therapeutic target for patients with NSCLC.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Phage-specific immunity impairs efficacy of bacteriophage targeting Vancomycin Resistant Enterococcus in a murine model

Bacteriophage therapy is a promising approach to address antimicrobial infections though questions remain regarding the impact of the immune response on clinical effectiveness. Here, we develop a mouse model to assess phage treatment using a cocktail of five phages from the Myoviridae and Siphoviridae families that target Vancomycin-Resistant Enterococcus gut colonization. Phage treatment significantly reduces fecal bacterial loads of Vancomycin-Resistant Enterococcus. We also characterize immune responses elicited following administration of the phage cocktail. While minimal innate responses are observed after phage administration, two rounds of treatment induces phage-specific neutralizing antibodies and accelerate phage clearance from tissues. Interestingly, the myophages in our cocktail induce a more robust neutralizing antibody response than the siphophages. This anti-phage immunity reduces the effectiveness of the phage cocktail in our murine model. Collectively, this study shows phage-specific immune responses may be an important consideration in the development of phage cocktails for therapeutic use.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8 + T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

A miniature CRISPR–Cas10 enzyme confers immunity by inhibitory signalling

Microbial and viral co-evolution has created immunity mechanisms involving oligonucleotide signalling that share mechanistic features with human antiviral systems1. In these pathways, including cyclic oligonucleotide-based antiphage signalling systems (CBASSs) and type III CRISPR systems in bacteria and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) in humans, oligonucleotide synthesis occurs upon detection of virus or foreign genetic material in the cell, triggering the antiviral response2, 3–4. Here, in an unexpected inversion of this process, we show that the CRISPR-related enzyme mCpol synthesizes cyclic oligonucleotides constitutively as part of an active mechanism that represses a toxic effector. Cell-based experiments demonstrated that the absence or loss of mCpol-produced cyclic oligonucleotides triggers cell death, preventing the spread of viruses that attempt immune evasion by depleting host cyclic nucleotides. Structural and mechanistic investigation revealed mCpol to be a di-adenylate cyclase whose product, c-di-AMP, prevents toxic oligomerization of the effector protein 2TMβ. Analysis of cells by fluorescence microscopy showed that lack of mCpol allows 2TMβ-mediated cell death due to inner membrane collapse. These findings unveil a powerful defence strategy against virus-mediated immune suppression, expanding our understanding of the role of oligonucleotides in immunity.

Doherty, Erin E↗

DOE OSTI2024

Structural basis for the activity and specificity of the immune checkpoint inhibitor lirilumab

The clinical success of immune checkpoint inhibitors has underscored the key role of the immune system in controlling cancer. Current FDA-approved immune checkpoint inhibitors target the regulatory receptor pathways of cytotoxic T-cells to enhance their anticancer responses. Despite an abundance of evidence that natural killer (NK) cells can also mediate potent anticancer activities, there are no FDA-approved inhibitors targeting NK cell specific checkpoint pathways. Lirilumab, the most clinically advanced NK cell checkpoint inhibitor, targets inhibitory killer immunoglobulin-like receptors (KIRs), however it has yet to conclusively demonstrate clinical efficacy. Here we describe the crystal structure of lirilumab in complex with the inhibitory KIR2DL3, revealing the precise epitope of lirilumab and the molecular mechanisms underlying KIR checkpoint blockade. Notably, the epitope includes several key amino acids that vary across the human population, and binding studies demonstrate the importance of these amino acids for lirilumab binding. These studies reveal how KIR variations in patients could influence the clinical efficacy of lirilumab and reveal general concepts for the development of immune checkpoint inhibitors targeting NK cells.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Analysis of intraspecies diversity reveals a subset of highly variable plant immune receptors and predicts their binding sites

The evolution of recognition specificities by the immune system depends on the generation of receptor diversity and on connecting the binding of new antigens with the initiation of downstream signaling. In plant immunity, the innate Nucleotide-Binding Leucine-Rich Repeat (NLR) receptor family enables antigen binding and immune signaling. In this study, we surveyed the NLR complements of 62 ecotypes of Arabidopsis thaliana and 54 lines of Brachypodium distachyon and identified a limited number of NLR subfamilies that show high allelic diversity. We show that the predicted specificity-determining residues cluster on the surfaces of Leucine-Rich Repeat domains, but the locations of the clusters vary among NLR subfamilies. By comparing NLR phylogeny, allelic diversity, and known functions of the Arabidopsis NLRs, we formulate a hypothesis for the emergence of direct and indirect pathogen-sensing receptors and of the autoimmune NLRs. These findings reveal the recurring patterns of evolution of innate immunity and can inform NLR engineering efforts.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Silencing of Dicer‐like protein 2a restores the resistance phenotype in the rice mutant, sxi4 ( suppressor of Xa21‐mediated immunity 4 )

SUMMARY The rice immune receptor XA21 confers resistance to Xanthomonas oryzae pv. oryzae ( Xoo ), and upon recognition of the RaxX21‐sY peptide produced by Xoo , XA21 activates the plant immune response. Here we screened 21 000 mutant plants expressing XA21 to identify components involved in this response, and reported here the identification of a rice mutant, sxi4, which is susceptible to Xoo. The sxi4 mutant carries a 32‐kb translocation from chromosome 3 onto chromosome 7 and displays an elevated level of DCL2a transcript, encoding a Dicer‐like protein . Silencing of DCL2a in the sxi4 genetic background restores resistance to Xoo . RaxX21‐sY peptide‐treated leaves of sxi4 retain the hallmarks of XA21‐mediated immune response. However, WRKY45‐1 , a known negative regulator of rice resistance to Xoo , is induced in the sxi4 mutant in response to RaxX21‐sY peptide treatment. A CRISPR knockout of a short interfering RNA (TE‐siRNA815) in the intron of WRKY45‐1 restores the resistance phenotype in sxi4 . These results suggest a model where DCL2a accumulation negatively regulates XA21‐mediated immunity by altering the processing of TE‐siRNA815.

Liu, Furong↗

DOE OSTI2026

Recurrent acquisition of nuclease-protease pairs in antiviral immunity

Antiviral immune systems diversify by integrating new genes into existing pathways, creating new mechanisms of viral resistance. We identified genes encoding a predicted nuclease paired with a trypsin-like protease repeatedly acquired by multiple, otherwise unrelated antiviral immune systems in bacteria. Cell-based and biochemical assays revealed that the nuclease is a proenzyme that cleaves DNA only after activation by its partner protease. Two distinct immune systems, Hachiman and AVAST (antiviral adenosine triphosphatase/nucleoside triphosphatase of the STAND superfamily, Avs), use the same mechanism of proteolytic activation despite their independent evolutionary origins. Examination of nuclease-protease inheritance patterns identified caspase-nuclease (canu) genomic loci that confer antiviral defense in a pathway reminiscent of eukaryotic caspase activation. These results uncover the coordinated activities of pronucleases and their activating proteases within different immune systems and show how coevolution enables defense system innovation.

Tuck, Owen T↗

DOE OSTI2025

De novo synthesis and near atomic resolution imaging of host immune receptors critical for pathogen recognition (Abbreviated Final Report)

The innate immune system serves as the body’s first line of defense against invading pathogens, responding rapidly through the deployment of immune cells at common sites of infection, such as the skin and airways. These immune-cell sentinels express a range of highly conserved receptors, including Toll-like receptors (TLRs), which recognize and bind to pathogen-derived components. This recognition event triggers intracellular signaling cascades that initiate and coordinate immune responses. Despite their significance, the complete structural characterization of full-length TLRs, including their extracellular domain (ECD), transmembrane domain (TMD), and Toll/interleukin-1 receptor (TIR) domain, remains incomplete. In this study, we examined the expression and isolation of human TLR4 incorporated into nanodiscs using two approaches: a cell-free synthesis system and a cell-based transfection strategy employing Expi293F cells derived from the human embryonic kidney lineage. Our findings demonstrate that NLP-bound human TLR4 produced via the cell-based method yielded functional protein suitable for time-resolved single-particle cryo-electron microscopy (cryo-EM). This advancement enables structural characterization of full-length TLR4, maintaining the integrity of its extracellular domain, transmembrane domain, and Toll/Interleukin-1 receptor (TIR) domain.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Detection of innate immune response modulating impurities (IIRMI) in therapeutic peptides and proteins: Impact of excipients

Unintended immunogenicity can affect the safety and efficacy of therapeutic proteins and peptides, so accurate assessments of immunogenicity risk can aid in the selection, development, and regulation of biologics. Product- and process- related impurities can act as adjuvants that activate the local or systemic innate immune response increasing the likelihood of product immunogenicity. Thus, assessing whether products have innate immune response modulating impurities (IIRMI) is a key component of immunogenicity risk assessments. Identifying trace levels of individual IIRMI can be difficult and testing individually for all potential impurities is not feasible. Therefore, to mitigate the risk, cell-based assays that use human blood cells or monocyte-macrophage reporter cell lines are being developed to detect minute quantities of impurities capable of eliciting innate immune activation. As these are cell-based assays, there is concern that excipients could blunt the cell responses, masking the presence of immunogenic IIRMI. Here, we explore the impact of frequently used excipients (non-ionic detergents, sugars, amino acids, bulking agents) on the sensitivity of reporter cell lines (THP-1- and RAW-Blue cells) and fresh human blood cells to detect purified TLR agonists as model IIRMI. We show that while excipients do not modulate the innate immune response elicited by TLR agonists in vivo, they can impact on the sensitivity of cell-based IIRMI assays. Reduced sensitivity to detect LPS, FSL-1, and other model IIRMI was also evident when testing 3 different recombinant drug products, product A (a representative mAb), B (a representative growth factor), C (a representative peptide), and their corresponding formulations. These results indicate that product formulations need to be considered when developing and validating cell-based assays for assessing clinically relevant levels of IIRMI in therapeutic proteins. Optimization of reporter cells, culture conditions and drug product concentration appear to be critical to minimize the impact of excipients and attain sensitive and reproducible assays.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Single-cell and spatiotemporal transcriptomic profiling of brain immune infiltration following Venezuelan equine encephalitis virus infection

Neurotropic alphaviruses such as Venezuelan equine encephalitis virus (VEEV) are critical human pathogens that continually expand to naïve populations and for which there are no licensed vaccines or therapeutics. VEEV is highly infectious via the aerosol route and is a recognized weaponizable biothreat that causes neurological disease in humans. The neuropathology of VEEV has been attributed to an inflammatory immune response in the brain yet the underlying mechanisms and specific immune cell populations involved are not fully elucidated. This study uses single-cell RNA sequencing to produce a comprehensive transcriptional profile of immune cells isolated from the brain over a time course of infection in a mouse model of VEEV. Analyses reveal differentially activated subpopulations of microglia, including a distinct type I interferon-expressing subpopulation. This is followed by the sequential infiltration of myeloid cells and cytotoxic lymphocytes, also comprising subpopulations with unique transcriptional signatures. We identify a subpopulation of myeloid cells that form a distinct localization pattern in the hippocampal region whereas lymphocytes are widely distributed, indicating differential modes of recruitment, including that to specific regions of the brain. Altogether, this study provides a high-resolution analysis of the immune response to VEEV in the brain and highlights potential avenues of investigation for therapeutics that target neuroinflammation in the brain.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Histopathological characteristics of PRRS and expression profiles of viral receptors in the piglet immune system

Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious viral disease that causes significant economic losses to the swine industry worldwide. PRRS virus (PRRSV) infection is a receptor-mediated endocytosis and replication process. The purpose of this study was to determine the localization and expression of four important PRRSV receptors in immunological organs of piglets. After piglets were infected with PRRSV, Hematoxylin and Eosin staining, immunofluorescence, and Western blot were used to perform histopathological examination and receptors distribution analysis. The results showed that PRRSV caused severe damage to the piglets’ immune organs, including atrophy of the thymus and swelling of lymph node. Histopathological lesions were mainly observed in the lung and lymph node and were characterized by interstitial pneumonia, collapsed follicles, exhaustion of germinal centers, and extensive hemorrhage. Immunofluorescence staining and Western blot results showed that the receptors of CD163 and NMHCII-A were mainly distributed in the thymus, hilar lymph nodes, and mesenteric lymph nodes. However, Sn and vimentin receptors were expressed at low levels in the immune organs of piglets. The distribution of the four receptors in the immune organs was more concentrated in the cortex but was more scattered in the medulla. Compared to the control group, the relative expression of the four receptors increased significantly in most immune organs after viral infection. In conclusion, our study examined the distribution and expression of four PRRSV receptors in immunological organs. We observed a significant increase in the expression of Sn, CD163, and vimentin following viral infection. These findings may provide potential targets for future antiviral reagent design or vaccine development.

Chen, Hong↗

NASA NTRS1992

Immune responsiveness and risk of illness in U.S. Air Force Academy cadets during basic cadet training

It has been proposed, but not confirmed, that environmental stressors alter immune function and increase the risk of viral infection among healthy individuals. This hypothesis was evaluated by examining the relationship among stress, immune function, and illness in 96 first-year U.S. Air Force Academy cadets during orientation and four weeks later during the stressful environment of basic cadet training (BCT). Perceived stress and well-being levels of cadets were assessed via questionnaire. Immune responsiveness was analyzed by PHA-stimulated thymidine uptake in mononuclear leucocytes and by serologic evidence of reactivation of the Epstein-Barr virus (EBV). Results showed significant declines in in vitro PHA-induced lymphocyte transformation (-35 percent)and subjective well-being (-19 percent) from orientation to BCT with corresponding, significant increases in perceived stress (+32 percent). Despite significantly altered in vitro immune responsiveness, there was no serologic evidence of EBV reactivation nor was there an association between these measures and risk of illness as determined by medical chart review and self-reported symptoms.

Lee, David J.↗

NASA NTRS1994

Spaceflight and immune responses of Rhesus monkeys

Evidence from both human and rodent studies indicates that alterations in immunological parameters occur after space flight. The objective of this project is to determine the effects of space flight on immune responses of Rhesus monkeys. The expected significance of the work is a determination of the range of immunological functions of the Rhesus monkey, a primate similar in many ways to man, affected by space flight. Changes in immune responses that could yield alterations in resistance to infection may be determined as well as the duration of alterations in immune responses. Additional information on the nature of cellular interactions for the generation of immune responses may also be obtained.

Sonnenfeld, Gerald↗

NASA NTRS1999

Sustained Partial Sleep Deprivation: Effects on Immune Modulation and Growth Factors

The vulnerability to medical emergencies is greatest in space where there are real limits to the availability or effectiveness of ground based assistance. Moreover, astronaut safety and health maintenance will be of increasing importance as we venture out into space for extended periods of time. It is therefore critical to understand the mechanisms of the regulatory physiology of homeostatic systems (sleep, circadian, neuroendocrine, fluid and nutritional balance) and the key roles played in adaptation. This synergy project has combined aims of the "Human Performance Factors, Sleep and Chronobiology Team"; the "Immunology, Infection and Hematology Team"; and the "Muscle Alterations and Atrophy Team", to broadly address the effects of long term sleep reduction, as is frequently encountered in space exploration, on neuroendocrine, neuroimmune and circulating growth factors. Astronaut sleep is frequently curtailed to averages of between 4- 6.5 hours per night. There is evidence that this amount of sleep is inadequate for maintaining optimal daytime functioning. However, there is a lack of information concerning the effects of chronic sleep restriction, or reduction, on regulatory physiology in general, and there have been no controlled studies of the cumulative effects of chronic sleep reduction on neuroendocrine and neuroimmune parameters. This synergy project represents a pilot study designed to characterize the effects of chronic partial sleep deprivation (PSD) on neuroendocrine, neuroimmune and growth factors. This project draws its subjects from two (of 18) conditions of the larger NSBRI project, "Countermeasures to Neurobehavioral Deficits from Cumulative Partial Sleep Deprivation During Space Flight", one of the projects on the "Human Performance Factors, Sleep and Chronobiology Team ". For the purposes of this study, to investigate the effects of chronic sleep loss on neuroendocrine and neuroimmune function, we have focused on the two extreme sleep conditions from this larger study: a 4.2 hour per night condition, and a 8.2 hour per night condition. During space flight, muscle mass and bone density are reduced, apparently due to loss of GH and IGF-I, associated with microgravity. Since >70% of growth hormone (GH) is secreted at night in normal adults, we hypothesized that the chronic sleep restriction to 4 hours per night would reduce GH levels as measured in the periphery. In this synergy project, in collaboration with the "Muscle Alterations and Atrophy Team ", we are measuring insulin-like growth factor-I (IGF-I) in peripheral circulation to test the prediction that it will be reduced by chronic sleep restriction. In addition to stress modulation of immune function, recent research suggests that sleep is also involved. While we all have the common experience of being sleepy when suffering from infection, and being susceptible to infection when not getting enough sleep, the mechanisms involved in this process are not understood and until recently have gone largely overlooked. We believe that the immune function changes seen in spaceflight may also be related to the cumulative effects of sleep loss. Moreover, in space flight, the possibility of compromised immune function or of the reactivation of latent viruses are serious potential hazards for the success of long term missions. Confined living conditions, reduced sleep, altered diet and stress are all factors that may compromise immune function, thereby increasing the risks of developing and transmitting disease. Medical complications, which would not pose serious problems on earth, may be disastrous if they emerged in space.

Mullington, Janet M.↗

NASA NTRS2002

Artificial Immune System Approaches for Aerospace Applications

Artificial Immune Systems (AIS) combine a priori knowledge with the adapting capabilities of biological immune system to provide a powerful alternative to currently available techniques for pattern recognition, modeling, design, and control. Immunology is the science of built-in defense mechanisms that are present in all living beings to protect against external attacks. A biological immune system can be thought of as a robust, adaptive system that is capable of dealing with an enormous variety of disturbances and uncertainties. Biological immune systems use a finite number of discrete "building blocks" to achieve this adaptiveness. These building blocks can be thought of as pieces of a puzzle which must be put together in a specific way-to neutralize, remove, or destroy each unique disturbance the system encounters. In this paper, we outline AIS models that are immediately applicable to aerospace problems and identify application areas that need further investigation.

KrishnaKumar, Kalmanje↗