Pilot Preference, Compliance, and Performance With an Airborne Conflict Management Toolset

A human-in-the-loop experiment was conducted at the NASA Ames and Langley Research Centers, investigating the En Route Free Maneuvering component of a future air traffic management concept termed Distributed Air/Ground Traffic Management (DAG-TM). NASA Langley test subject pilots used the Autonomous Operations Planner (AOP) airborne toolset to detect and resolve traffic conflicts, interacting with subject pilots and air traffic controllers at NASA Ames. Experimental results are presented, focusing on conflict resolution maneuver choices, AOP resolution guidance acceptability, and performance metrics. Based on these results, suggestions are made to further improve the AOP interface and functionality

Emerging Perspectives of Synaptic Biomarkers in ALS and FTD

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions and genetic mutations. Both diseases involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated with synaptic function or structure, offer insights into disease mechanisms, progression, and treatment responses. These biomarkers can detect disease early, track its progression, and evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and blood, correlating with disease progression. TDP-43 is another key ALS biomarker, its mislocalization linked to synaptic dysfunction. In FTD, TDP-43 and tau proteins are studied as biomarkers. Synaptic biomarkers like neuronal pentraxins (NPs), including neuronal pentraxin 2 (NPTX2), and neuronal pentraxin receptor (NPTXR), offer insights into FTD pathology and cognitive decline. Advanced technologies, like machine learning (ML) and artificial intelligence (AI), aid biomarker discovery and drug development. Challenges in this research include technological limitations in detection, variability across patients, and translating findings from animal models. ML/AI can accelerate discovery by analyzing complex data and predicting disease outcomes. Synaptic biomarkers offer early disease detection, personalized treatment strategies, and insights into disease mechanisms. While challenges persist, technological advancements and interdisciplinary efforts promise to revolutionize the understanding and management of ALS and FTD. This review will explore the present comprehension of synaptic biomarkers in ALS and FTD and discuss their significance and emphasize the prospects and obstacles

Fast-Time Evaluations of Airborne Merging and Spacing in Terminal Arrival Operations

NASA researchers are developing new airborne technologies and procedures to increase runway throughput at capacity-constrained airports by improving the precision of inter-arrival spacing at the runway threshold. In this new operational concept, pilots of equipped aircraft are cleared to adjust aircraft speed to achieve a designated spacing interval at the runway threshold, relative to a designated lead aircraft. A new airborne toolset, prototypes of which are being developed at the NASA Langley Research Center, assists pilots in achieving this objective. The current prototype allows precision spacing operations to commence even when the aircraft and its lead are not yet in-trail, but are on merging arrival routes to the runway. A series of fast-time evaluations of the new toolset were conducted at the Langley Research Center during the summer of 2004. The study assessed toolset performance in a mixed fleet of aircraft on three merging arrival streams under a range of operating conditions. The results of the study indicate that the prototype possesses a high degree of robustness to moderate variations in operating conditions

One Agent Too Many: User Perspectives on Approaches to Multi-agent Conversational AI

Conversational agents have been gaining increasing popularity in recent years. Influenced by the widespread adoption of task-oriented agents such as Apple Siri and Amazon Alexa, these agents are being deployed into various applications to enhance user experience. Although these agents promote "ask me anything" functionality, they are typically built to focus on a single or finite set of expertise. Given that complex tasks often require more than one expertise, this results in the users needing to learn and adopt multiple agents. One approach to alleviate this is to abstract the orchestration of agents in the background. However, this removes the option of choice and flexibility, potentially harming the ability to complete tasks. In this paper, we explore these different interaction experiences (one agent for all) vs (user choice of agents) for conversational AI. We design prototypes for each, systematically evaluating their ability to facilitate task completion. Through a series of conducted user studies, we show that users have a significant preference for abstracting agent orchestration in both system usability and system performance. Additionally, we demonstrate that this mode of interaction is able to provide quality responses that are rated within 1% of human-selected answers

Effect of food deprivation and hormones of glucose homeostasis on the acetyl CoA carboxylase activity in mouse brain: a potential role of acc in the regulation of energy balance

We studied the regulation of brain acetyl CoA carboxylase (ACC) activity during food deprivation and under the influence of hormones of glucose homeostasis: glucagon and insulin. Mice were deprived of food and water for time periods of 1, 3, 6, 9, 12 and 24 hours and were then allowed to re-feed for 5, 30 and 60 minutes. Mice that were deprived for up to 6 h, and then re-fed for 60 min, consumed the same amount of food compared to the ad libitum (control) animals. However, after 9 h of deprivation, mice consumed only 50% of food present even after 1 h of re-feeding, compared to the controls. The ACC activity was measured in the whole mouse brain of controls and after 1, 3, 6, 9, 12, and 24 h of food deprivation. Brain extracts assayed from control mice expressed an ACC activity of 0.988 ± 0.158 fmol/min/mg tissue without citrate and 0.941 ± 0.175 fmol/min/mg tissue with citrate. After 1 h of food deprivation, the total ACC activity without citrate decreased to 0.575 ± 0.087 fmol/min/mg and in the presence of citrate, 0.703 ± 0.036 fmol/min/mg activity was measured. The citrate-dependent ACC activity decreased over time, with only 0.478 ± 0.117 fmol/min/mg of activity remaining after 24 h. Intraperitoneal (i.p.) injections of insulin, glucagon and phosphate buffered saline (PBS) were performed and whole brain ACC activity measured. After hormone administration, there were no significant differences in ACC activity in the presence of citrate. However, in the absence of citrate, there was a significant 20% decrease in ACC activity with glucagon (1.36 ± 0.09 fmol/min/mg) and a 33% increase with insulin (2.49 ± 0.11 fmol/min/mg) injections compared to PBS controls (1.67 ± 0.08 fmol/min/mg). Neuropeptide Y (NPY) levels of corresponding brain extracts were measured by ELISA (OD) using anti-NPY antibody and showed an 18% decrease upon insulin injection (0.093 ± 0.019) and a 50% increase upon glucagon injection (0.226 ± 0.084) as compared to controls injected with PBS (0.114 ± 0.040). Thus, we postulate that the changes in ACC levels under metabolic conditions would result in a fluctuation of malonyl CoA levels, and subsequent modulation of NPY levels and downstream signaling

Association of Micronutrients and Prevalence of Antibodies in Hyperthyroidism

Thyroid hormones play a pivotal role in the overall physiological and developmental function of the human body. Alterations in thyroid hormones drastically affect regular metabolic processes as well as physical well-being. Thyroid alterations directly influence the functioning of all major body systems including cardiovascular, neurological, gastrointestinal, etc. The thyroid hormonal imbalance is primarily classified into two major conditions: hyperthyroidism and hypothyroidism. The present chapter details the pathology of thyroid imbalance in the context of human reproductive health, autoimmunity, and micronutrient imbalance. Some novel micronutrient associations independent of iodine deficiencies are discussed. Additionally, the early predictive capability of the anti-TPO antibody as well as other autoimmune correlations are discussed. Given its role in reproductive health, the associations of various sex hormones with thyroid function were also explored

Autonomous aircraft operations using RTCA guidelines for airborne conflict management

Abstract A human-in-the-loop experiment was performed at the NASA Langley Research Center to study the feasibility of DAG-TM autonomous aircraft operations in highly constrained airspace. The airspace was constrained by a pair of special-use airspace (SUA) regions on either side of the pilot's planned route. Traffic flow management (TFM) constraints were imposed as a required time of arrival and crossing altitude at an en route fix. Key guidelines from the RTCA Airborne Conflict Management (ACM) concept were applied to autonomous aircraft operations for this experiment. These concepts included the RTCA ACM definitions of distinct conflict detection and collision avoidance zones, and the use of a graded system of conflict alerts for the flight crew. Three studies were conducted in the course of the experiment. The first study investigated the effect of hazard proximity upon pilot ability to meet constraints and solve conflict situations. The second study investigated pilot use of the airborne tools when faced with an unexpected loss of separation (LOS). The third study explored pilot interactions in an over-constrained conflict situation, with and without priority rules dictating who should move first. Detailed results from these studies were presented at the 5 th USA/Europe Air Traffic Management R&D Seminar (ATM2003). This overview paper focuses on the integration of the RTCA ACM concept into autonomous aircraft operations in highly constrained situations, and provides an overview of the results presented at the ATM2003 seminar. These results, together with previously reported studies, continue to support the feasibility of autonomous aircraft operations

A mouse model with widespread expression of the C9orf72-linked glycine-arginine dipeptide displays non-lethal ALS/FTD-like phenotypes

Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes in these mice, including mild motor neuron loss, but no TDP-43 mis-localization, as well as motor and cognitive impairments. We suggest that this model can serve as the foundation for phenotypic exacerbation through second-hit forms of stress

The Nuclear Import Receptor Kapβ2 Modifies Neurotoxicity Mediated by Poly(GR) in C9orf72-linked ALS/FTD

Expanded intronic G4C2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice