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At least 685 records · Page 38

Regime-oriented causal model evaluation of Atlantic–Pacific teleconnections in CMIP6

The climate system and its spatio-temporal changes are strongly affected by modes of long-term internal variability, like the Pacific decadal variability (PDV) and the Atlantic multidecadal variability (AMV). As they alternate between warm and cold phases, the interplay between PDV and AMV varies over decadal to multidecadal timescales. Here, we use a causal discovery method to derive fingerprints in the Atlantic–Pacific interactions and to investigate their phase-dependent changes. Dependent on the phases of PDV and AMV, different regimes with characteristic causal fingerprints are identified in reanalyses in a first step. In a second step, a regime-oriented causal model evaluation is performed to evaluate the ability of models participating in the Coupled Model Intercomparison Project Phase 6 (CMIP6) in representing the observed changing interactions between PDV, AMV and their extra-tropical teleconnections. The causal graphs obtained from reanalyses detect a direct opposite-sign response from AMV to PDV when analyzing the complete 1900–2014 period and during several defined regimes within that period, for example, when AMV is going through its negative (cold) phase. Reanalyses also demonstrate a same-sign response from PDV to AMV during the cold phase of PDV. Historical CMIP6 simulations exhibit varying skill in simulating the observed causal patterns. Generally, large-ensemble (LE) simulations showed better network similarity when PDV and AMV were out of phase compared to other regimes. Also, the two largest ensembles (in terms of number of members) were found to contain realizations with similar causal fingerprints to observations. For most regimes, these same models showed higher network similarity when compared to each other. This work shows how causal discovery on LEs complements the available diagnostics and statistical metrics of climate variability to provide a powerful tool for climate model evaluation.

54 ENVIRONMENTAL SCIENCES↗

Drug-induced kidney injury: challenges and opportunities

Abstract Drug-induced kidney injury (DIKI) is a frequently reported adverse event, associated with acute kidney injury, chronic kidney disease, and end-stage renal failure. Prospective cohort studies on acute injuries suggest a frequency of around 14%–26% in adult populations and a significant concern in pediatrics with a frequency of 16% being attributed to a drug. In drug discovery and development, renal injury accounts for 8 and 9% of preclinical and clinical failures, respectively, impacting multiple therapeutic areas. Currently, the standard biomarkers for identifying DIKI are serum creatinine and blood urea nitrogen. However, both markers lack the sensitivity and specificity to detect nephrotoxicity prior to a significant loss of renal function. Consequently, there is a pressing need for the development of alternative methods to reliably predict drug-induced kidney injury (DIKI) in early drug discovery. In this article, we discuss various aspects of DIKI and how it is assessed in preclinical models and in the clinical setting, including the challenges posed by translating animal data to humans. We then examine the urinary biomarkers accepted by both the US Food and Drug Administration (FDA) and the European Medicines Agency for monitoring DIKI in preclinical studies and on a case-by-case basis in clinical trials. We also review new approach methodologies (NAMs) and how they may assist in developing novel biomarkers for DIKI that can be used earlier in drug discovery and development.

Connor, Skylar (ORCID:0000000233479180)↗

Photon counting with intensified charge coupled device (ICCD) – I. In-depth detector characterization

While the adsorption properties of transition metal catalysts have been widely studied, leading to the discovery of various scaling relations, descriptors of catalytic activity, and well-established computational models, a similar understanding of semiconductor catalysts has not yet been achieved. In this work, we present a high-throughput density functional theory investigation into the adsorption properties of 5 oxides of interest to the photocatalytic CO 2 reduction reaction: TiO 2 (rutile and anatase), SrTiO 3 , NaTaO 3 , and CeO 2 . Using a systematic approach, we exhaustively identify unique surfaces and construct adsorption structures to undergo geometry optimizations. We then perform a data-driven analysis, which reveals the presence of weak adsorption energy scaling relations, the propensity of adsorbates of interest to interact with oxygen surface sites, and the importance of slab deformation upon adsorption. Our findings are presented in the context of experimental observations and in comparison to previously studied classes of catalysts, such as pure metals and tellurium-containing semiconductors, and reinforce the need for a comprehensive approach to the study of site-specific surface phenomena on semiconductors.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Systematic computational study of oxide adsorption properties for applications in photocatalytic CO 2 reduction

While the adsorption properties of transition metal catalysts have been widely studied, leading to the discovery of various scaling relations, descriptors of catalytic activity, and well-established computational models, a similar understanding of semiconductor catalysts has not yet been achieved. In this work, we present a high-throughput density functional theory investigation into the adsorption properties of 5 oxides of interest to the photocatalytic CO 2 reduction reaction: TiO 2 (rutile and anatase), SrTiO 3 , NaTaO 3 , and CeO 2 . Using a systematic approach, we exhaustively identify unique surfaces and construct adsorption structures to undergo geometry optimizations. We then perform a data-driven analysis, which reveals the presence of weak adsorption energy scaling relations, the propensity of adsorbates of interest to interact with oxygen surface sites, and the importance of slab deformation upon adsorption. Our findings are presented in the context of experimental observations and in comparison to previously studied classes of catalysts, such as pure metals and tellurium-containing semiconductors, and reinforce the need for a comprehensive approach to the study of site-specific surface phenomena on semiconductors.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Antiviral discovery using sparse datasets by integrating experiments, molecular simulations, and machine learning

Computational methods have demonstrated success in identifying virucidal agents, effectively contributing to the discovery of novel virucidal molecules. In this study, we developed a machine learning (ML) model, trained on a small dataset, to predict inhibitors of human enterovirus 71 (EV71), a pathological agent that causes severe disease in children and immunocompromised adults. Despite the dataset’s limitation, comprising of only 36 compounds tested, our ML framework demonstrated significant predictive capability. Notably, experimental validation revealed that five out of the eight compounds predicted by our model from the Chinese cosmetic material list exhibited virucidal activity. The inhibitor effects displayed by the main active compounds were further confirmed by molecular dynamics simulation. This underscores the potential of our AI-driven approach to bypass data constraints in identifying active molecules against viral pathogens.

60 APPLIED LIFE SCIENCES↗

Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48 h), good (>50%), or unusable (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002, JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.

60 APPLIED LIFE SCIENCES↗

The Enterprise , a massive transposon carrying Spok meiotic drive genes

The genomes of eukaryotes are full of parasitic sequences known as transposable elements (TEs). Here, we report the discovery of a putative giant tyrosine-recombinase-mobilized DNA transposon, Enterprise, from the model fungus Podospora anserina. Previously, we described a large genomic feature called the Spok block which is notable due to the presence of meiotic drive genes of the Spok gene family. The Spok block ranges from 110 kb to 247 kb and can be present in at least four different genomic locations within P. anserina, despite what is an otherwise highly conserved genome structure. We propose that the reason for its varying positions is that the Spok block is not only capable of meiotic drive but is also capable of transposition. More precisely, the Spok block represents a unique case where the Enterprise has captured the Spoks, thereby parasitizing a resident genomic parasite to become a genomic hyperparasite. Furthermore, we demonstrate that Enterprise (without the Spoks) is found in other fungal lineages, where it can be as large as 70 kb. Lastly, we provide experimental evidence that the Spok block is deleterious, with detrimental effects on spore production in strains which carry it. This union of meiotic drivers and a transposon has created a selfish element of impressive size in Podospora, challenging our perception of how TEs influence genome evolution and broadening the horizons in terms of what the upper limit of transposition may be.

59 BASIC BIOLOGICAL SCIENCES↗

Novel small molecule FGF 23 inhibitors increase serum phosphate and improve skeletal abnormalities in Hyp mice

We report that excess fibroblast growth factor 23 (FGF23) causes hereditary hypophosphatemic rickets, such as X-linked hypophosphatemia (XLH) and tumor induced osteomalacia (TIO). A small molecule that specifically binds to FGF23 to prevent activation of the FGFR/a-Klotho complex has potential advantages over the currently approved systemically administered FGF23 blocking antibody. Using structure-based drug design we previously identified ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a small molecule antagonist for FGF23. Additional structure-activity studies developed a series of ZINC13407541 analogues with enhanced drug-like properties. In this study, we tested in a pre-clinical Hyp mouse homologue of XLH a direct connect analogue (8n) [(E)-2-(4-(tert-butyl)phenyl)cyclopent-1-ene-1-carbaldehyde oxime] that exhibited the greatest stability in microsomal assays, and 13a [(E)-2-((E)-4-methylstyryl)benzaldehyde oxime] that exhibited increased in vitro potency. Using cryo-electron microscopy (Cryo-EM) structure and computational docking, we identified a key binding residue (Q156) of the FGF23 antagonists, ZINC13407541 and its analogues (8n and 13a) in the N-terminal domain of FGF23 protein. Site-directed mutagenesis and bimolecular fluorescence complementation (BiFC)-fluorescence resonance energy transfer (FRET) assay confirmed the binding site of these three antagonists. We found that pharmacological inhibition of FGF23 with either of these compounds blocked FGF23 signaling and increased serum phosphate and 1,25(OH)2D concentrations in Hyp mice. Long-term parenteral treatment with 8n or 13a also enhanced linear bone growth, increased mineralization of bone, and narrowed the growth plate in Hyp mice. The more potent 13a compound had greater therapeutic effects in Hyp mice. Further optimization of these FGF23 inhibitors may lead to versatile drugs to treat excess FGF23-mediated disorders.

60 APPLIED LIFE SCIENCES↗

Leverage modern artificial intelligence (AI) enabled systems for waste reduction

Manufacturing industries continue to face challenges in reducing waste, as upstream strategies such as source reduction and product redesign require a deeper understanding of processes compared to conventional recycling methods. Recent advancements in artificial intelligence (AI) and machine learning (ML) have opened new opportunities to integrate modern computational techniques with traditional waste minimization strategies. This paper explores AI-enabled approaches for product redesign, source reduction, and recycling that can significantly reduce waste generation while improving efficiency and sustainability. AI-driven material substitution and lightweighting in product design enable discovery of novel materials with optimized properties, reducing waste without compromising performance. Reinforcement learning models optimize process parameters, raw material specifications, and machine sequencing to minimize production losses, while Industrial Internet of Things (IIoT) systems paired with AI analytics enhance real-time waste tracking, predictive maintenance, and quality inspection. Furthermore, AI-based demand forecasting and production planning reduce overproduction and excess inventory, as demonstrated in industrial applications. In recycling, ML-powered pattern recognition and robotic sorting technologies achieve higher accuracy in waste segregation, directly improving recycling efficiency. Complementary solutions such as smart bins and AI-enabled waste pickup scheduling optimize collection logistics, reducing both costs and emissions. Although implementation requires upfront investment in infrastructure and training, the long-term benefits include higher material efficiency, reduced waste, improved product quality, and stronger sustainability outcomes across the supply chain. By leveraging AI-enabled systems, manufacturers can align waste minimization efforts with circular economy principles, creating scalable solutions for both industry and society.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗

Leveraging Artificial Intelligence to Expedite Antibody Design and Enhance Antibody–Antigen Interactions

This perspective sheds light on the transformative impact of recent computational advancements in the field of protein therapeutics, with a particular focus on the design and development of antibodies. Cutting-edge computational methods have revolutionized our understanding of protein–protein interactions (PPIs), enhancing the efficacy of protein therapeutics in preclinical and clinical settings. Central to these advancements is the application of machine learning and deep learning, which offers unprecedented insights into the intricate mechanisms of PPIs and facilitates precise control over protein functions. Despite these advancements, the complex structural nuances of antibodies pose ongoing challenges in their design and optimization. Our review provides a comprehensive exploration of the latest deep learning approaches, including language models and diffusion techniques, and their role in surmounting these challenges. We also present a critical analysis of these methods, offering insights to drive further progress in this rapidly evolving field. The paper includes practical recommendations for the application of these computational techniques, supplemented with independent benchmark studies. These studies focus on key performance metrics such as accuracy and the ease of program execution, providing a valuable resource for researchers engaged in antibody design and development. Through this detailed perspective, we aim to contribute to the advancement of antibody design, equipping researchers with the tools and knowledge to navigate the complexities of this field.

59 BASIC BIOLOGICAL SCIENCES↗

DATA-DRIVEN DISCOVERY OF DYNAMICS FROM TIME-RESOLVED COHERENT SCATTERING

This software implements a data-driven framework to uncover mechanistic models of dynamics directly from time-resolved coherent X-ray scattering measurements. It employs neural differential equations to parameterize unknown real-space dynamics and incorporates a computational scattering forward model to relate real-space predictions to reciprocal-space observations.

Zhou, Tao↗

Imaging photopolarimeter on Pioneer Saturn

Results of Pioneer 11 imaging photopolarimeter observations of Saturn, its rings, and Titan are presented. The imaging photopolarimeter is a pointable telescope with an aperture of 2.5 cm and passbands of 390 to 500 to 720 nm which uses the spin of the spacecraft to scan across an object. Images of the Saturn system and of the rings are presented, and the absence of a D ring, structures in the C, B and A rings and the Cassini division and the discoveries of the F ring and the provisionally named Pioneer division separating it from the A ring are reported. A mean particle size less than 15 meters is estimated from estimates of total ring mass and the optical depth of the B ring. The discovery of the satellite 1979 S 1 at 2.53 Saturn radii is also noted. Models of the vertical aerosol structure of Saturn's atmosphere are compared with the polarization data, and it is indicated that the density of cloud particles decreases with altitude with a scale height about one fourth that of the gas, and that an optical depth of one is to be found at 750 mbar.

Gehrels, T.↗

The heavy ion composition in 3HE-rich solar flares

The 3He-rich flares show a tendency to be enriched in heavy ions, and that this enrichment covers the charge range through Fe. The discovery of this association was responsible, in part, for the discarding of 3He enrichment models which involved spallation or thermonuclear reactions, since such models were unable to produce heavy nuclei enhancement. Results of a survey of heavy nucleus abundances observed in 66 3He-rich flares which occurred over the period October 1978 to June 1982 are presented.

Mason, G. M.↗

Occurrence of oxidized components in Qingzhen enstatite chondrite

It is shown that the most unequilibrated enstatite chondrite, Qingzhen, contains a population of enstatite grains which appear to have formed under more oxidizing nebular conditions than the bulk of the meteorite, which is highly reduced. These grains are black in transmitted light because of the presence of micron-sized inclusions of Ni-poor, Cr-rich metal, and occur either isolated within the matrix or in chondrule interiors. The textural occurrence of these grains argues against their having been introduced during collision of Qingzhen with an oxidized meteorite. Most likely, they originated in the same general nebular neighborhood of the reduced bulk Qingzhen material and were subsequently transported into the reducing environment either before or during the process of chondrule formation. The discovery of this once-oxidized material in Qingzhen posed significant constraints on existing models of formation of reduced matter in the solar system.

Rambaldi, E. R.↗

Stability of Castering Wheels for Aircraft Landing Gears

A theoretical study was made of the shimmy of castering wheels. The theory is based on the discovery of a phenomenon called kinematic shimmy. Experimental checks, use being made of a model having low-pressure tires, are reported and the applicability of the results to full scale is discussed. Theoretical methods of estimating the spindle viscous damping and the spindle solid friction necessary to avoid shimmy are given. A new method of avoiding shimmy -- lateral freedom -- is introduced.

Kantrowitz, Arthur↗

An Open, Snow-based Hydrologic System on Noachian Mars

Properties of Noachian valley networks on Mars suggest that the conditions under which they formed were marginal for liquid water formation. The networks are sparsely scattered, poorly dissected, and tend to be small; a majority occupy areas only a few hundred kilometers in extent. Models in which networks formed by mass wasting are contra-indicated by the discovery of channels within the valleys. Greenhouse hypotheses for the stability of liquid water have foundered on familiar problems: first, a very substantial CO2 atmosphere would be required to bring global average conditions to 273 K; the CO2 should still be present in extensive carbonate deposits that have not been detected. Explanations that call upon groundwater sapping are hampered by the need for a hydrologic system to recharge the groundwater system, which effectively reinstates the need for a heavy CO2 atmosphere. Based upon field experience and geomorphic similarities between drainage developed in the periglacial terrain in and around the Haughton impact structure, Devon Island, Nuunavuut, Canada, we have suggested that some of the channel networks may have formed either subglacially, or as ice marginal structures.

Zent, A. P.↗

Exploring and Analyzing Climate Variations Online by Using NASA MERRA-2 Data at GES DISC

NASA Giovanni (Goddard Interactive Online Visualization ANd aNalysis Infrastructure) (http:giovanni.sci.gsfc.nasa.govgiovanni) is a web-based data visualization and analysis system developed by the Goddard Earth Sciences Data and Information Services Center (GES DISC). Current data analysis functions include Lat-Lon map, time series, scatter plot, correlation map, difference, cross-section, vertical profile, and animation etc. The system enables basic statistical analysis and comparisons of multiple variables. This web-based tool facilitates data discovery, exploration and analysis of large amount of global and regional remote sensing and model data sets from a number of NASA data centers. Long term global assimilated atmospheric, land, and ocean data have been integrated into the system that enables quick exploration and analysis of climate data without downloading, preprocessing, and learning data. Example data include climate reanalysis data from NASA Modern-Era Retrospective analysis for Research and Applications, Version 2 (MERRA-2) which provides data beginning in 1980 to present; land data from NASA Global Land Data Assimilation System (GLDAS), which assimilates data from 1948 to 2012; as well as ocean biological data from NASA Ocean Biogeochemical Model (NOBM), which provides data from 1998 to 2012. This presentation, using surface air temperature, precipitation, ozone, and aerosol, etc. from MERRA-2, demonstrates climate variation analysis with Giovanni at selected regions.

knowledge base↗