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DOE OSTI2022

Concentration-response gene expression analysis in zebrafish reveals phenotypically-anchored transcriptional responses to retene

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants and are associated with human disease. Canonically, many PAHs induce toxicity via activation of the aryl hydrocarbon receptor (AHR) pathway. While the interaction between PAHs and the AHR is well-established, understanding which AHR-regulated transcriptional effects directly result in observable phenotypes and which are adaptive or benign is important to better understand PAH toxicity. Retene is a frequently detected PAH in environmental sampling and has been associated with AHR2-dependent developmental toxicity in zebrafish, though its mechanism of toxicity has not been fully elucidated. To interrogate transcriptional changes causally associated with retene toxicity, we conducted whole-animal RNA sequencing at 48 hours post-fertilization after exposure to eight retene concentrations. The concentrations were selected to produce effects ranging from no phenotype to mortality and malformations in 100% of animals at 5 days post-fertilization. We identified a concentration-response relationship between retene teratogenicity and differential gene expression in both number of DEGs and magnitude of expression change. Elevated expression of cyp1a at retene concentrations below the threshold for teratogenicity suggested that while cyp1a expression is a sensitive biomarker of AHR activation, it may be too sensitive to serve as a biomarker of AHR-dependent teratogenicity. Genes differentially expressed at only non-teratogenic concentrations were enriched for transforming growth factor-ß (TGF-ß) signaling pathway disruption while DEGs identified at only teratogenic concentrations were significantly enriched for response to xenobiotic stimulus and reduction-oxidation reaction activity. DEGs which spanned both non-teratogenic and teratogenic concentrations showed similar disrupted biological processes to those unique to teratogenic concentrations, indicating these processes were disrupted at low exposure concentrations. Gene co-expression network analysis identified several gene modules, including those associated with PAHs and AHR2 activation. One, Module 7, was strongly enriched for AHR2-associated genes and contained the strongest responses to retene. Benchmark concentration (BMC) of Module 7 genes identified a median BMC of 7.5 µM, nearly the highest retene concentration with no associated teratogenicity, supporting the hypothesis that Module 7 genes are largely responsible for retene toxicity.

Toxin, Zebrafish, Retene, Transcriptomics, network↗

DOE OSTI2024

The safety of magnetic resonance imaging contrast agents

Gadolinium-based contrast agents are increasingly used in clinical practice. While these pharmaceuticals are verified causal agents in nephrogenic systemic fibrosis, there is a growing body of literature supporting their role as causal agents in symptoms associated with gadolinium exposure after intravenous use and encephalopathy following intrathecal administration. Gadolinium-based contrast agents are multidentate organic ligands that strongly bind the metal ion to reduce the toxicity of the metal. The notion that cationic gadolinium dissociates from these chelates and causes the disease is prevalent among patients and providers. We hypothesize that non-ligand-bound (soluble) gadolinium will be exceedingly low in patients. Soluble, ionic gadolinium is not likely to be the initial step in mediating any disease. The Kidney Institute of New Mexico was the first to identify gadolinium-rich nanoparticles in skin and kidney tissues from magnetic resonance imaging contrast agents in rodents. In 2023, they found similar nanoparticles in the kidney cells of humans with normal renal function, likely from contrast agents. We suspect these nanoparticles are the mediators of chronic toxicity from magnetic resonance imaging contrast agents. This article explores associations between gadolinium contrast and adverse health outcomes supported by clinical reports and rodent models.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Female “Paradox” in Atrial Fibrillation—Role of Left Truncation Due to Competing Risks

Female sex in patients with atrial fibrillation (AF) is a controversial and paradoxical risk factor for stroke—controversial because it increases the risk of stroke only among older women of some ethnicities and paradoxical because it appears to contradict male predominance in cardiovascular diseases. However, the underlying mechanism remains unclear. We conducted simulations to examine the hypothesis that this sex difference is generated non-causally through left truncation due to competing risks (CR) such as coronary artery diseases, which occur more frequently among men than among women and share common unobserved causes with stroke. We modeled the hazards of stroke and CR with correlated heterogeneous risk. We assumed that some people died of CR before AF diagnosis and calculated the hazard ratio of female sex in the left-truncated AF population. In this situation, female sex became a risk factor for stroke in the absence of causal roles. The hazard ratio was attenuated in young populations without left truncation and in populations with low CR and high stroke incidence, which is consistent with real-world observations. This study demonstrated that spurious risk factors can be identified through left truncation due to correlated CR. Female sex in patients with AF may be a paradoxical risk factor for stroke.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

GW190814's Secondary Component with Mass 2.50–2.67 M ⊙ as a Superfast Pulsar

Using Stergioulas's RNS code for investigating fast pulsars with Equation of States (EOSs) on the causality surface (where the speed of sound equals that of light) of the high-density EOS parameter space satisfying all known constraints from both nuclear physics and astrophysics, we show that one possible explanation for the GW190814's secondary component of mass (2.50-2.67) M ⊙ is that it is a super-fast pulsar spinning faster than 971 Hz about 42% below its Kepler frequency. If confirmed, it would be the fastest pulsar with the highest mass observed presently. There is a large and physically allowed EOS parameter space below the causality surface where pulsars heavier than 2.50 M ⊙ are supported if they can rotate even faster with critical frequencies depending strongly on the high-density behavior of nuclear symmetry energy.

79 ASTRONOMY AND ASTROPHYSICS↗

DOE OSTI2025

Constraining aerosol–cloud adjustments by uniting surface observations with a perturbed parameter ensemble

Abstract. Aerosol–cloud interactions (ACIs) are the largest source of uncertainty in inferring the magnitude of future warming consistent with the observational record. The effective radiative forcing due to ACI (ERFaci) is dominated by liquid clouds and is composed of two terms: the change in cloud albedo due to redistributing liquid over a larger number of cloud droplets (Nd) and the change in cloud macrophysical properties due to changes in cloud microphysics. These terms are, respectively, referred to as the radiative forcing due to ACI (RFaci) and aerosol–cloud adjustments. While the magnitude of RFaci is uncertain, its sign is confidently negative and results in a cooling in the historical record. In contrast, the adjustment of cloud liquid water path (LWP) to enhanced Nd and associated radiative forcing is uncertain in sign. Increased LWP in response to increased Nd is consistent with precipitation suppression, while decreased LWP in response to increased Nd is consistent with enhanced evaporation from cloud top. Observational constraints of these processes are poor in part because of causal ambiguity in the relationship between Nd and LWP. To better understand this relationship, precipitation (P), Nd, and LWP surface observations from the Eastern North Atlantic (ENA) atmospheric observatory are combined with the output from a perturbed parameter ensemble (PPE) hosted in the Community Atmosphere Model version 6 (CAM6). This allows for causal interpretation of observed covariability. Observations of precipitation and cloud from ENA constrain the range of possible LWP aerosol–cloud adjustments relative to the prior from the PPE by 15 %, resulting in a global value that is confidently positive (a historical cooling) ranging from 2.1 to 6.9 g m−2. It is found that observed covariability between Nd and LWP is dominated by coalescence scavenging and that this observed covariability is not strongly related to aerosol–cloud adjustments.

54 ENVIRONMENTAL SCIENCES↗

NASA NTRS1973

Critique of fluid theory of magnetospheric phenomena

It is pointed out that the fluid theory has been successful in magnetospheric problems (such as the shape of the magnetopause) which involve basic considerations such as the conservation of particles, of momentum, and of energy, but that it is inadequate for other problems (such as the energization of auroral particles). Difficulties arise from the fact that it is not always possible to specify 'a volume of plasma' because particles do not remain as neighbors. Misuse of the fluid theory has led to a number of fallacies, such as the idea that the causal order of physical events in cosmic electrodynamics is the reverse of that in the familiar laboratory electrodynamics. This mistaken idea comes from a confusion of a mathematical sequence of calculations with the causal order. A plea is made for a common sense approach to magnetospheric and auroral problems wherein the fluid theory is used whenever it can, but where it is not expected to be adequate for all occasions.

Heikkila, W. J.↗

NASA NTRS1976

A correlation polarimeter for noise-like signals

Optimum estimation (tracking) of the polarization plane of a linearly polarized electromagnetic wave is determined when the signal is a narrow-band Gaussian random process with a polarization plane angle which is also a Gaussian random process. This model is compared to previous work and is applicable to space communication. The estimator performs a correlation operation similar to an amplitude-comparison monopulse angle tracker, giving the name correlation polarimeter. Under large signal-to-noise ratio (SNR), the estimator is causal. Performance of the causal correlation polarimeter is evaluated for arbitrary SNR. Optimum precorrelation filtering is determined. With low SNR, the performance of this system is far better than that of previously developed systems. Practical implementation is discussed. A scheme is given to reduce the effect of linearly polarized noise.

Ohlson, J. E.↗

NASA NTRS1977

Noncausal propagation in spin-0 theories with external field interactions

The two-component Sakata-Taketani (ST) spin-0 theory and the single-component Klein-Gordon theory are obtained from the five-component Duffin-Kemmer-Petiau (DKP) theory with six types of external field interactions by means of a Peirce decomposition. Whereas the DKP equation manifests the covariance, the ST equation manifests the causal properties. In particular, the presence of noncausal wave propagation when there is coupling to a second-rank tensor field is apparent from the form of the ST equation, in which the coefficients of all the space derivatives depend on the external field. The results indicate that the causal properties of higher-spin equations should also be obvious when they are expressed in 2(2J + 1)-component Schroedinger form

Guertin, R. F.↗

NASA NTRS1977

Noncausal effects in relativistic wave equations

Manifestly covariant wave equations describing particles with a unique mass and spin can, for certain types of external-field interactions, possess noncausal solutions. The paper reports a procedure for applying Pierce decomposition of all six couplings expressed in the Duffin-Kemmer-Petiau spin-0 formula. This treatment converts the equation to a form in which the causal properties are apparent. The conditions under which the causal properties of higher-spin equations can be made manifest are discussed.

Guertin, R. F.↗

NASA NTRS1980

Transmitted sound field due to an impulsive line acoustic source bounded by a plate followed by a vortex sheet

The propagation of sound due to a line acoustic source in the moving stream across a semiinfinite vortex sheet which trails from a rigid plate is examined in a linear theory for the subsonic case. A solution for the transmitted sound field is obtained with the aid of multiple integral transforms and the Wiener-Hopf technique for both the steady state (time harmonic) and initial value (impulsive source) situations. The contour of inverse transform and hence the decomposition of the functions are determined through causality and radiation conditions. The solution obtained satisfies causality and the full Kutta conditions. The transmitted sound field is composed of two waves in both the stady state and initial value problems. One is the wave scattered from the edge of the plate which is associated with the bow wave and the instability wave. These waves exist in the downstream sectors. The other is the wave transmitted through the vortex sheet which is also associated with the instability wave. Regional divisions of the transmitted sound field are identified.

Miura, T.↗

NASA NTRS1982

Candidate Species Selection and Controlled Environment Injuries

Research was undertaken to attempt to identify the causal agents for intumescences that develop on many different species of plants in controlled environments. Concentration and filtration procedures were not successful in identifying any particular compounds. The injury was found to develop, even though the atmosphere for the plants is filtered through activated charcoal, potassium permanganate, or is subjected to catalytic combustion at 450 C. Thus, the causal agent is apparently either an oxidized compound or specific element, or the result of some unrecognized variation in physical conditions around the plants. The research has demonstrated that the injury is controlled to a significant extent by temperature. Growing temperatures of 20 degrees and 25 degrees C resulted in serious injury on plants, but temperatures of 30 C resulted in very little injury.

Tibbitts, T. W.↗

NASA NTRS1985

Management behavior, group climate and performance appraisal at NASA

The relationships among manager behavior, group climate and managerial effectiveness are examined. Survey data were collected from 435 GM14-15 managers and their subordinates at NASA concerning management practices and perceptions of the group environment. Performance ratings of managers were obtained from their superiors. The results strongly supported a causal model in which subordinates' climate perceptions mediate the effects of manager behavior on performance. That is, the development of group climate provides the process through which the effects of manager practices may be understood. Analyses also revealed that the function performed by a manager and his group (e.g., research) influenced the specific nature of the causal dynamics. Some implications of the results for management training and development are discussed.

Manderlink, G.↗

NASA NTRS1988

A methodology for the synthesis of robust feedback systems

A new methodology is developed for the synthesis of linear, time-variant (LTI) controllers for multivariable LTI systems. The resulting closed-loop system is nominally stable and exhibits a known level of performance. In addition, robustness of the feedback system is guaranteed, i.e., stability and performance are retained in the presence of multiple unstructured uncertainty blocks located at various points in the feedback loop. The design technique is referred to as the Causality Recovery Methodology (CRM). The CRM relies on the Youla parameterization of all stabilizing compensators to ensure nominal stability of the feedback system. A frequency-domain inequality in terms of the structured singular value mu defines the robustness specification. The optimal compensator, with respect to the mu condition, is shown to be noncausal in general. The aim of the CRM is to find a stable, causal transfer function matrix that approximates the robustness characteristics of the optimal solution. The CRM, via a series of infinite-dimensional convex programs, produces a closed-loop system whose performance robustness is at least as good as that of any initial design. The algorithm is approximated by a finite dimensional process for the purposes of implementation. Two numerical examples confirm the potential viability of the CRM concept; however, the robustness improvement comes at the expense of increased computational burden and compensator complexity.

Milich, David Albert↗

NASA NTRS1987

Predictive monitoring research: Summary of the PREMON system

Traditional approaches to monitoring are proving inadequate in the face of two important issues: the dynamic adjustment of expectations about sensor values when the behavior of the device is too complex to enumerate beforehand, and the selective but effective interpretation of sensor readings when the number of sensors becomes overwhelming. This system addresses these issues by building an explicit model of a device and applying common-sense theories of physics to model causality in the device. The resulting causal simulation of the device supports planning decisions about how to efficiently yet reliably utilize a limited number of sensors to verify correct operation of the device.

Doyle, Richard J.↗

NASA NTRS1987

Stochastic control of infinite dimensional systems in Hilbert space: A factorization perspective

A factorization perspective on problems of optimal causal estimation and optimal causal control of linear stochastic systems defined on an infinite-dimensional Hilbert space is presented. A separation principle is derived for the case in which the system input/output map is generated by an abstract evolution operator. The factorization formalism allows for an essentially algebraic approach to these problems.

Milman, Mark M.↗

NASA NTRS1989

An innovations approach to decoupling of multibody dynamics and control

The problem of hinged multibody dynamics is solved using an extension of the innovations approach of linear filtering and prediction theory to the problem of mechanical system modeling and control. This approach has been used quite effectively to diagonalize the equations for filtering and prediction for linear state space systems. It has similar advantages in the study of dynamics and control of multibody systems. The innovations approach advanced here consists of expressing the equations of motion in terms of two closely related processes: (1) the innovations process e, a sequence of moments, obtained from the applied moments T by means of a spatially recursive Kalman filter that goes from the tip of the manipulator to its base; (2) a residual process, a sequence of velocities, obtained from the joint-angle velocities by means of an outward smoothing operations. The innovations e and the applied moments T are related by means of the relationships e = (I - L)T and T = (I + K)e. The operation (I - L) is a causal lower triangular matrix which is generated by a spatially recursive Kalman filter and the corresponding discrete-step Riccati equation. Hence, the innovations and the applied moments can be obtained from each other by means of a causal operation which is itself casually invertible.

Rodriguez, G.↗

NASA NTRS1990

Dynamic test input generation for multiple-fault isolation

Recent work is Causal Reasoning has provided practical techniques for multiple fault diagnosis. These techniques provide a hypothesis/measurement diagnosis cycle. Using probabilistic methods, they choose the best measurements to make, then update fault hypotheses in response. For many applications such as computers and spacecraft, few measurement points may be accessible, or values may change quickly as the system under diagnosis operates. In these cases, a hypothesis/measurement cycle is insufficient. A technique is presented for a hypothesis/test-input/measurement diagnosis cycle. In contrast to generating tests a priori for determining device functionality, it dynamically generates tests in response to current knowledge about fault probabilities. It is shown how the mathematics previously used for measurement specification can be applied to the test input generation process. An example from an efficient implementation called Multi-Purpose Causal (MPC) is presented.

Schaefer, Phil↗

NASA NTRS1990

A diagnosis system using object-oriented fault tree models

Spaceborne computing systems must provide reliable, continuous operation for extended periods. Due to weight, power, and volume constraints, these systems must manage resources very effectively. A fault diagnosis algorithm is described which enables fast and flexible diagnoses in the dynamic distributed computing environments planned for future space missions. The algorithm uses a knowledge base that is easily changed and updated to reflect current system status. Augmented fault trees represented in an object-oriented form provide deep system knowledge that is easy to access and revise as a system changes. Given such a fault tree, a set of failure events that have occurred, and a set of failure events that have not occurred, this diagnosis system uses forward and backward chaining to propagate causal and temporal information about other failure events in the system being diagnosed. Once the system has established temporal and causal constraints, it reasons backward from heuristically selected failure events to find a set of basic failure events which are a likely cause of the occurrence of the top failure event in the fault tree. The diagnosis system has been implemented in common LISP using Flavors.

Iverson, David L.↗