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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.

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At least 73 records · Page 4

Modeling aerosol bolus inhalations in the human lung with the multiple path particle deposition model: Comparison with experimental data

Existing one-dimensional (1D) models of aerosol dosimetry often ignore mixing mechanisms of inhaled aerosols during their transport in the lung. This mixing or aerosol dispersion results from different physical mechanisms in different regions of the lung. It is a higher order effect, which cannot be directly captured in 1D modeling approaches, and thus is sometimes modeled as a diffusive process. Here, in this study, we improved our recently developed alveolar mixing module incorporated in the multiple path particle dosimetry model (MPPD) to account for flow irreversibility and particle trapping in the alveolar spaces, as well as mixing occurring in the tracheobronchial region. This new version of MPPD was coupled with CFPD-based predictions of aerosol bolus dispersion in the oral airway. The model was used to predict the deposition, dispersion, and mode shift of aerosol bolus inhaled at different penetration depths within the lung for breathing patterns and particle size matching those used in a previous experimental study (Darquenne et al., 2016). Even though a quite simplified approach was used, the computations appear to describe subject-specific and test-specific experimental data reasonably well. The proposed combined dispersion-deposition model can be a useful tool for targeted drug delivery and also for exposure health risk assessment.

MPPD↗

Novel CHI3L1 ‐Associated Angiogenic Phenotypes Define Glioma Microenvironments: Insights From Multi‐Omics Integration

ABSTRACT The CHI3L1 signaling pathway significantly influences glioma angiogenesis, but its role in the tumor microenvironment (TME) remains elusive. We propose a novelCHI3L1‐associated vascular phenotype classification for glioma through integrative analyses of multiple datasets with bulk and single‐cell transcriptome, genomics, digital pathology, and clinical data. We investigated the biological characteristics, genomic alterations, therapeutic vulnerabilities, and immune profiles within these phenotypes through a comprehensive multi‐omics approach. We constructed the vascular‐related risk (VR) score based onCHI3L1‐associated vascular signatures (CAVS) identified by machine learning algorithms. Utilizing unsupervised consensus clustering, gliomas were stratified into three distinct vascular phenotypes: Cluster A, marked by high vascularization and stromal activation with a relatively low levels of tumor‐infiltrating lymphocytes (TILs); Cluster B, characterized by moderate vascularization and stromal activity, coupled with a high density of TILs; and Cluster C, defined by low vascularization and sparse immune cell infiltration. We observed that the CAVS effectively indicated glioma‐associated angiogenesis and immune suppression by single‐cell RNA‐seq analysis. Moreover, the high‐VR‐score group exhibited enhanced angiogenic activity, reduced immune response, resistance to immunotherapy, and poorer clinical outcomes. The VR score independently predicted glioma prognosis and, combined with a nomogram, provided a robust clinical decision‐making tool. Potential drug prediction based on transcription factors for high‐risk patients was also performed. Our study reveals thatCHI3L1‐associated vascular phenotypes shape distinct immune landscapes in gliomas, offering insights for optimizing therapeutic strategies to improve patient outcomes.

Oncology↗

Theory of antimotion sickness drug mechanisms.

The results of a series of antimotion sickness drug evaluations indicates that drugs with central anticholinergic actions and drugs that increase central sympathetic activity are effective against motion sickness. The combination of these actions produces a synergistic effect against motion sickness. The effect of these medications on central acetylcholine or on norepinephrine could alter a balance between the neurons in the vestibular and reticular areas which influence motion sickness and also sympathetic and parasympathetic reactions. It is suggested that this could be their mechanism of action in preventing motion sickness.

Wood, D. C.↗

Anti-motion-sickness therapy

Neither alterations in environmental temperature nor moderate intake of alcohol was found to alter susceptibility to motion sickness in subjects exposed to rotation in the Pensacola slow rotation room. Scopolamine with d-amphetamine was found to be the most effective preparation for the prevention of motion sickness under the experimental conditions of the studies reported here. Promethazine in combination with d-amphetamine was in the same range of effectiveness. Drug actions suggest that acetylcholine and norepinephrine may be involved in motion sickness.

Wood, C. D.↗

Effects of Zoledronate and Mechanical Loading during Simulated Weightlessness on Bone Structure and Mechanical Properties

Space flight modulates bone remodeling to favor bone resorption. Current countermeasures include an anti-resorptive drug class, bisphosphonates (BP), and high-force loading regimens. Does the combination of anti-resorptives and high-force exercise during weightlessness have negative effects on the mechanical and structural properties of bone? In this study, we implemented an integrated model to mimic mechanical strain of exercise via cyclical loading (CL) in mice treated with the BP Zoledronate (ZOL) combined with hindlimb unloading (HU). Our working hypothesis is that CL combined with ZOL in the HU model induces additive structural and mechanical changes. Thirty-two C57BL6 mice (male,16 weeks old, n8group) were exposed to 3 weeks of either HU or normal ambulation (NA). Cohorts of mice received one subcutaneous injection of ZOL (45gkg), or saline vehicle, prior to experiment. The right tibia was axially loaded in vivo, 60xday to 9N in compression, repeated 3xweek during HU. During the application of compression, secant stiffness (SEC), a linear estimate of slope of the force displacement curve from rest (0.5N) to max load (9.0N), was calculated for each cycle once per week. Ex vivo CT was conducted on all subjects. For ex vivo mechanical properties, non-CL left femurs underwent 3-point bending. In the proximal tibial metaphysis, HU decreased, CL increased, and ZOL increased the cancellous bone volume to total volume ratio by -26, +21, and +33, respectively. Similar trends held for trabecular thickness and number. Ex vivo left femur mechanical properties revealed HU decreased stiffness (-37),and ZOL mitigated the HU stiffness losses (+78). Data on the ex vivo Ultimate Force followed similar trends. After 3 weeks, HU decreased in vivo SEC (-16). The combination of CL+HU appeared additive in bone structure and mechanical properties. However, when HU + CL + ZOL were combined, ZOL had no additional effect (p0.05) on in vivo SEC. Structural data followed this trend with ZOL not modulating trabecular thickness in CL + NAHU mice. In summary, our integrated model simulates the combination of weightlessness, exercise-induced mechanical strain, and anti-resorptive treatment that astronauts experience during space missions. Based on these results, we conclude that, at the structural and stiffness level, zoledronate treatment during simulated spaceflight does not impede the skeletal response to axial compression. In contrast to our hypothesis, our data show that zoledronate confers no additional mechanical or structural benefit beyond those gained from cyclical loading.

Mechanical Loading↗

Evaluation of possible interaction among drugs contemplated for use during manned space flights

Possible interactions among drugs contemplated for use during manned spaceflights have been studied in several animal species. The following seven drugs were investigated: nitrofurantoin, chloral hydrate, hexobarbital, phenobarbital, flurazepam, diphenoxylate, and phenazopyridine. Particular combinations included: chloral hydrate, hexabarbital or flurazepam with nitrofurantoin; phenobarbital or flurazepam with phenazopyridine; and diphenoxylate with two does formulations of nitrofurantoin. Studies were carried out in several species to determine whether induction of liver microsomal enzymes would increase the tendency of phenazopyridine to produce methemoglobin in vivo. Animals were premedicated with phenobarbital, a known inducer of azoreductase, and in a separate experiment with flurazepam, before administration of phenazopyridine. Methemoglobin production was determined in each animal after receiving phenazopyridine. No evidence was found for increased production of methemoglobin in the rat, dog, or rabbit that could be attributed to increased amounts of microsomal enzymes.

Source record↗

Evaluation of possible interaction among drugs contemplated for use during manned space flights. Part 1: Summary from progress report dated 31 October 1973. Part 2: Progress report for the period November 1973 to June 1974

Possible interactions among drugs contemplated for use during manned spaceflights have been studied in several animal species. The following seven drugs were investigated: nitrofurantoin, chloral hydrate, hexobarbital, phenobarbital, flurazepam, diphenoxylate, and phenazopyridine. Particular combinations included: chloral hydrate, hexobarbital or flurazepam with nitrofurantoin; phenobarbital or flurazepam with phenazopyridine; and diphenoxylate with two dose formulations of nitrofurantoin. The mechanism of action and an explanation of the interaction between diphenoxylate and nitrofurantoin still remains unclear. In man, the interaction does not appear to be significant, affecting only two subjects out of six and with only one dose formulation (Furadantin).

Source record↗

A goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions

While many researchers can design knockdown and knockout methodologies to remove a gene product, this is mainly untrue for new chemical inhibitor designs that empower multifunctional DNA Damage Response (DDR) networks. Here, we present a robust Goldilocks (GL) computational discovery protocol to efficiently innovate inhibitor tools and preclinical drug candidates for cellular and structural biologists without requiring extensive virtual screen (VS) and chemical synthesis expertise. By computationally targeting DDR replication and repair proteins, we exemplify the identification of DDR target sites and compounds to probe cancer biology. Our GL pipeline integrates experimental and predicted structures to efficiently discover leads, allowing early-structure and early-testing (ESET) experiments by many laboratories. By employing an efficient VS protocol to examine protein-protein interfaces (PPIs) and allosteric interactions, we identify ligand binding sites beyond active sites, leveraging in silico advances for molecular docking and modeling to screen PPIs and multiple targets. A diverse 3,174 compound ESET library combines Diamond Light Source DSI-poised, Protein Data Bank fragments, and FDA-approved drugs to span relevant chemotypes and facilitate downstream hit evaluation efficiency for academic laboratories. Two VS per library and multiple ranked ligand binding poses enable target testing for several DDR targets. This GL library and protocol can thus strategically probe multiple DDR network targets and identify readily available compounds for early structural and activity testing to overcome bottlenecks that can limit timely breakthrough drug discoveries. By testing accessible compounds to dissect multi-functional DDRs and suggesting inhibitor mechanisms from initial docking, the GL approach may enable more groups to help accelerate discovery, suggest new sites and compounds for challenging targets including emerging biothreats and advance cancer biology for future precision medicine clinical trials.

59 BASIC BIOLOGICAL SCIENCES↗

Evaluation of a new antinauseant drug for the prevention of motion sickness

The new drug, AHR 5645B, together with other drugs was evaluated in tests, conducted with eight male subjects, concerning its ability to prevent motion sickness. It was found that AHR 5645B, used in doses of 20, 50, and 100 mg, was not efficacious in preventing experimental motion sickness. A combination of 50 mg meclizine and 25 mg ephedrine sulfate produced the best results. Favorable results were also obtained with a combination of 12.5 mg promethazine hydrochloride and 12.5 mg ephedrine sulfate. The findings in the reported experiment point to the difficulty of identifying a highly efficacious antimotion sickness drug for everyone.

Graybiel, A.↗

Transient histone deacetylase inhibition reveals cell type invariant and specific effects of chromatin decondensation on irradiation response

Radiation therapy plays a prominent role in breast cancer treatment, but the high doses of radiation damage both healthy and cancerous cells. Therefore, additional research is needed into combination therapies that could preferentially radiosensitize cancer cells compared to surrounding healthy tissue without causing deleterious side effects. Histone deacetylase inhibitor drugs (HDACis) have been tested as radiosensitizers in both basic research and clinical trials, but the long exposure time typically used in these treatments and the lack of matched healthy cell controls often leave aspects of their mechanism of action unclear. Here, we show that transient (2 h) trichostatin A (TSA) treatment of cancerous and non-tumorigenic breast epithelial cell lines increases immediate DNA damage and decreases long term cell viability in both cell types at high radiation doses. Transient TSA treatment also causes an increase in DNA damage signals after 5 Gy X-rays in other cancer and healthy cell types: A375 melanoma cells and BJ5-ta fibroblasts. This suggests that chromatin decompaction acts to increase cellular vulnerability to initial DNA damage from high doses of radiation in a cell type independent manner that does not rely on changes to DNA repair pathways caused by longer TSA treatment. However, responses to lower doses of radiation and long term survival are more cell type specific: only MCF7 cells experience an effect of TSA on DNA damage after 1 Gy X-ray radiation while MCF10a cells experience somewhat more evident cell viability effects of combined TSA and radiation treatment long term.

Li, Heng [Biochemistry & Cellular and Molecular Bi↗

Exploring the Effects of Intersubunit Interface Mutations on Virus-Like Particle Structure and Stability

Virus-like particles (VLPs) from bacteriophage MS2 provide a platform to study protein self-assembly and create engineered systems for drug delivery. Here, we aim to understand the impact of intersubunit interface mutations on the local and global structure and function of MS2-based VLPs. In previous work, our lab identified locally supercharged double mutants [T71K/G73R] that concentrate positive charge at capsid pores, enhancing uptake into mammalian cells. To study the effects of particle size on cellular internalization, we combined these double mutants with a single point mutation [S37P] that was previously reported to switch particle geometry from T = 3 to T = 1 icosahedral symmetry. These new variants retained their enhanced cellular uptake activity and could deliver small-molecule drugs with efficacy levels similar to our first-generation capsids. Surprisingly, these engineered triple mutants exhibit increased thermostability and unexpected geometry, producing T = 3 particles instead of the anticipated T = 1 assemblies. Transmission electron microscopy revealed various capsid assembly states, including wild-type (T = 3), T = 1, and rod-like particles, that could be accessed using different combinations of these point mutations. Molecular dynamics experiments recapitulated the structural rationale in silico for the single point mutation [S37P] forming a T = 1 virus-like particle and showed that this assembly state was not favored when combined with mutations that favor rod-like architectures. Through this work, we investigated how interdimer interface dynamics influence VLP size and morphology and how these properties affect particle function in applications such as drug delivery.

59 BASIC BIOLOGICAL SCIENCES↗

Agent-Based Model of Combined Community- and Jail-Based Take-Home Naloxone Distribution

Importance Opioid-related overdose accounts for almost 80 000 deaths annually across the US. People who use drugs leaving jails are at particularly high risk for opioid-related overdose and may benefit from take-home naloxone (THN) distribution. Objective To estimate the population impact of THN distribution at jail release to reverse opioid-related overdose among people with opioid use disorders. Design, Setting, and Participants This study developed the agent-based Justice-Community Circulation Model (JCCM) to model a synthetic population of individuals with and without a history of opioid use. Epidemiological data from 2014 to 2020 for Cook County, Illinois, were used to identify parameters pertinent to the synthetic population. Twenty-seven experimental scenarios were examined to capture diverse strategies of THN distribution and use. Sensitivity analysis was performed to identify critical mediating and moderating variables associated with population impact and a proxy metric for cost-effectiveness (ie, the direct costs of THN kits distributed per death averted). Data were analyzed between February 2022 and March 2024. Intervention Modeled interventions included 3 THN distribution channels: community facilities and practitioners; jail, at release; and social network or peers of persons released from jail. Main Outcomes and Measures The primary outcome was the percentage of opioid-related overdose deaths averted with THN in the modeled population relative to a baseline scenario with no intervention. Results Take-home naloxone distribution at jail release had the highest median (IQR) percentage of averted deaths at 11.70% (6.57%-15.75%). The probability of bystander presence at an opioid overdose showed the greatest proportional contribution (27.15%) to the variance in deaths averted in persons released from jail. The estimated costs of distributed THN kits were less than $\$$15 000 per averted death in all 27 scenarios. Conclusions and Relevance This study found that THN distribution at jail release is an economical and feasible approach to substantially reducing opioid-related overdose mortality. Training and preparation of proficient and willing bystanders are central factors in reaching the full potential of this intervention.

Tatara, Eric [Argonne National Laboratory (ANL), A↗

Experimental motion sickness - Efficacy of transdermal scopolamine plus ephedrine

A double-blind, placebo-controlled study compared the efficacy of transdermal therapeutic system-scopolamine administered alone and combined with ephedrine sulfate given orally in doses of 12.5, 25, and 50 mg. Eight normal male students were exposed to stressful accelerations in a slow-rotation room after receiving 10 apparently identical treatments comprising the four drugs and six placebos. Efficacy of the drug was defined in terms of the placebo range and categorized as beneficial, inconsequential, or detrimental. None of the effects was detrimental. Overall beneficial effects were 60% for transdermal therapeutic system-scopolamine (plus placebo) and 57% for the three transdermal therapeutic system-scopolamine plus ephedrine combinations.

Graybiel, A.↗

Taxane recovery from cells of Taxus in micro- and hypergravity

Cell suspension cultures of Taxus cuspidata produce taxanes that are released from the outer surface of cells into the culture medium as free and bound alkaloids. Paclitaxel (Taxol (TM)), is an anti-cancer drug in short supply. It has a taxane ring derived from baccatin III and a C-13 phenylisoserine side-chain. This drug is produced over a wide range of gravitational forces. Monoclonal and polyclonal antibodies to paclitaxel, baccatin III, and the C-13 phenylisoserine side chain were combined in multiple-labeling studies to localize taxanes and paclitaxel on cell surfaces or on particles released into the culture medium. Bioreactor vessel design altered the composition of taxanes recovered from cells in simulated microgravity. At 10(-2) and 2x10(-4)g, taxane recovery was reduced but biomass growth and percent paclitaxel was significantly increased. At 1 to 24g, growth was reduced with a significant recovery of total taxanes with low percent paclitaxel. Bound paclitaxel was also localized in endonuclease-rich fragmenting nuclei of individual apoptotic cells. A model is presented comprising TCH (touch) genes encoding enzymes that modify taxane-bearing xylan residues in cell walls, the calcium-sensing of gravitational forces by the cytoplasm, and the predisposition of nuclei to apoptosis. This integrates the adaptive physiological and biochemical responses of drug-producing genomes with gravitational forces.

Plants, Medicinal/chemistry/cytology↗

Towards Mitigating Electron Beam-Induced Damage in MOFs Using Low Dose Electron Microscopy for In-Situ Room-Temperature Measurements

Metal-Organic Frameworks (MOFs) have emerged as a versatile class of materials with applications in gas storage and separation, catalysis, and drug delivery [1]. Understanding their damage mechanisms in under various environmental conditions is crucial for optimizing performance and stability [2]. This study employs a combination of Length Structural Coherence (LSC) analysis in electron scattering and Electron Energy Loss Spectroscopy (EELS) to elucidate the damage mechanisms in two representative MOFs. MIL101(Fe), and MIL101(Cr). Here, the primary objective is to reveal structural and chemical changes that occur under electron beam irradiation in Scanning Transmission Electron Microscopy (STEM), both in the pristine state and during in-situ CO and CO 2 adsorption. By combining LSC in Radial Distribution Function (RDF) analysis with EELS, comprehensive insights into the nanoscale alterations are obtained and correlated to the electron dose rate.

dos Santos, Gabriel T. [Northwestern University, E↗

Use of Novel Light Sources and Melatonin Delivery Systems in the Maintenance of Temporal Organization of Physiological and Behavioral Circadian Rhythms

The synchronization of physiological and behavioral rhythms are controlled by an endogenous biological clock. It is generally accepted that environmental lighting is the strongest entrainer of this clock. The pineal gland is an important physiological transducer of environmental lighting via systemic melatonin secretion. We have used a novel light source using light emitting diode (LED) technology to entrain circadian rhythms in rats, and propose a novel percutaneous exogenous melatonin delivery system to entrain rat rhythms. We used 5 groups of Sprague-Dawley rats (175-350 g; N = 8/group) and showed normal entrainment of gross locomotor activity, feeding, and drinking circadian rhythms at light intensities varying from 80 lux to 0.1 lux (22.4 to 0.03 sq cm). To improve the delivery of melatonin across the skin stratum corneum it was formulated in a suitable vehicle in a transdermal drug delivery system. Various saturated and unsaturated fatty acids were used E, akin penetration enhancers. Our best vehicle formulation was achieved with a combination-of ethano1:water (60:40) along with 5% oleic acid as the enhancer. This formulation mixture was studied using Franz diffusion cell (0.636 sq cm diffusional area) and 1 cu cm dorsal skin isolated from Sprague Dawley rats. Our results showed that oleic acid in combination with the water ethanol mixture improved the flux of melatonin by more than 18 fold. The lag time for melatonin permeation was 2-3 hrs and the peak concentrations were achieved in 8-10 hrs. Our approaches in the future will involve the use of our transdermal melatonin delivery system and under the influence of LED light and microgravity.

Winget, C. M.↗

RLMolLM: Reinforcement Learning-Enhanced Language Model Framework for Inverse Molecular Design

Inverse molecular design faces significant challenges due to vast chemical space and complex property requirements. While language models show promise for molecular generation, they struggle with validity, multi-property optimization, and structural constraints. This work presents RLMolLM, a reinforcement learning framework combining Proximal Policy Optimization (PPO) with genetic algorithms to address these limitations. Our approach optimizes multiple user-specified properties including quantitative estimates of drug-likeness (QED), synthetic accessibility (SA), and ADMET (absorption, distribution, metabolism, excretion, and toxicity) endpoints without requiring complete model retraining, while maintaining capability for scaffold-constrained generation where specific substructures must be preserved. We outperform state-of-the-art methods for molecular optimization, achieving best QED scores across GDB13, Moses, and Zinc datasets with up to 31% improvement over previous methods while maintaining excellent validity, uniqueness, and novelty metrics. For simultaneous multi-property optimization, our framework achieves substantial improvements in ADMET properties including 4.5-fold reduction in hERG toxicity and enhanced Caco-2 permeability compared to Moses dataset. Under structural constraints, the framework significantly improves molecular validity while preserving scaffolds and effectively optimizing properties. In conclusion, this versatile solution advances pharmaceutical and materials molecular design through effective integration of reinforcement learning and genetic algorithms with multi-property optimization and scaffold preservation.

Genetic algorithms↗