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At least 181 records · Page 10

Evaluating the limitations of Bayesian metabolic control analysis

AbstractBayesian Metabolic Control Analysis (BMCA) has emerged as a promising framework for inferring metabolic control coefficients in data-limited scenarios by integrating Bayesian inference with linlog rate laws. However, its predictive accuracy and limitations remain underexplored. This study systematically evaluates BMCA’s ability to infer elasticity values, flux control coefficients (FCCs), and concentration control coefficients (CCCs) under varying data availability conditions using three synthetic metabolic network models. Our findings highlight the strengths and weaknesses of BMCA, guiding its application in metabolic engineering and emphasizing the need for methodological refinements.Author summaryUnderstanding how enzymes control metabolic pathways is crucial for optimizing biomanufacturing and synthetic biology applications. Bayesian Metabolic Control Analysis (BMCA) is a promising computational method that integrates Bayesian inference with metabolic control analysis to estimate key control parameters, even in cases with limited experimental data. However, the accuracy and limitations of BMCA remain unclear. In this study, we systematically evaluate BMCA using three synthetic metabolic networks to determine how different types of physiological data impact its predictive performance. We find that BMCA requires flux and enzyme concentration data for accurate predictions, while external metabolite concentrations contribute little. Additionally, BMCA fails to predict elasticity values beyond a magnitude of 1.5 and reliably infer allosteric regulation, even when strong regulatory interactions exist. In addition, BMCA does not accurately rank metabolic control points, which may limit its utility in identifying key enzymes in engineered pathways. Our work provides practical insights into when and how BMCA can be applied, guiding future research in metabolic modeling and control analysis.

Shin, Janis (ORCID:0000000216572455)↗

Low-energy 17 O(𝑛,𝛾)⁢ 18 O reaction within the microscopic potential model and its role for the weak 𝑟 process

The neutron radiative capture reaction 17 O ⁡(𝑛,𝛾) ⁢18 O plays a pivotal role in both nuclear structure studies and astrophysical nucleosynthesis, particularly in the formation of elements during hydrostatic and explosive stellar environments. We calculated the 17 O ⁡(𝑛,𝛾) ⁢18 O cross section within the Skyrme Hartree-Fock potential model and analyzed electric dipole 𝐸⁢1 transitions to both positive- and negative-parity states below the α-decay threshold in 18 O. Our cross sections are significantly different from the data available in commonly used libraries. We further investigate the impact of the new calculated cross section on weak 𝑟-process nucleosynthesis using large-scale reaction network calculations across a wide range of electron fractions and entropies. Our results show that the 17 O ⁡(𝑛,𝛾) ⁢18 O reaction rate significantly influences the production of first 𝑟-process peak elements, such as strontium, under specific astrophysical conditions. This study highlights the importance of accurate nuclear data for light isotopes in modeling heavy-element synthesis and provides updated reaction rates for future nucleosynthesis simulations.

6 ≤ A ≤ 19↗

Learning together: Towards foundation models for machine learning interatomic potentials with meta-learning

Abstract The development of machine learning models has led to an abundance of datasets containing quantum mechanical (QM) calculations for molecular and material systems. However, traditional training methods for machine learning models are unable to leverage the plethora of data available as they require that each dataset be generated using the same QM method. Taking machine learning interatomic potentials (MLIPs) as an example, we show that meta-learning techniques, a recent advancement from the machine learning community, can be used to fit multiple levels of QM theory in the same training process. Meta-learning changes the training procedure to learn a representation that can be easily re-trained to new tasks with small amounts of data. We then demonstrate that meta-learning enables simultaneously training to multiple large organic molecule datasets. As a proof of concept, we examine the performance of a MLIP refit to a small drug-like molecule and show that pre-training potentials to multiple levels of theory with meta-learning improves performance. This difference in performance can be seen both in the reduced error and in the improved smoothness of the potential energy surface produced. We therefore show that meta-learning can utilize existing datasets with inconsistent QM levels of theory to produce models that are better at specializing to new datasets. This opens new routes for creating pre-trained, foundation models for interatomic potentials.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

Cosmological preference for a negative neutrino mass

The most precise determination of the sum of neutrino masses from cosmological data, derived from analysis of the cosmic microwave background (CMB) and baryon acoustic acoustic oscillations (BAO) from the Dark Energy Spectroscopic Instrument (DESI), favors a value below the minimum inferred from neutrino flavor oscillation experiments. We explore which data is most responsible of this puzzling aspect of the current constraints on neutrino mass and whether it is related to other anomalies in cosmology. We demonstrate conclusively that the preference for negative neutrino masses is a consequence of larger than expected lensing of the CMB in both the two- and four-point lensing statistics. Furthermore, we show that this preference is robust to changes in likelihoods of the BAO and CMB optical depth analyses given the available data. We then show that this excess clustering is not easily explained by changes to the expansion history and is likely distinct from the preference for for dynamical dark energy in DESI BAO data. Finally, we discuss how future data may impact these results, including an analysis of Planck CMB with mock DESI 5-year data. Here, we conclude that the negative neutrino mass preference is likely to persist even as more cosmological data is collected in the near future.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

A primer on forest structure measurement with lidar for ecologists

Light detection and ranging (lidar) technology has fundamentally advanced the way we measure forest structure, facilitating new insights into ecological processes. Lidar for forest ecology applications is deployed on multiple types of platforms that operate from the ground, air, or space, and each has associated strengths and limitations. Ideally, the choice of what kind of lidar to use in a particular study should be guided by the ecological question of interest; however, practical considerations of cost, data availability, and processing tools can be equally important. This synthesis is a practical introduction to how different lidar platforms characterize forest structure (e.g., tree size/location, wood volume, branching structure, aboveground biomass, leaf properties), designed for a general audience of ecologists (not remote sensing scientists) seeking an accessible introduction to the use of lidar. We also provide examples of novel ecological insights from recent lidar research and describe current limitations and areas of expected improvement. Last, we include an appendix of data collected from terrestrial, mobile, unoccupied aerial system, airplane, and satellite lidar platforms within a common temperate forest area, with associated code to allow new lidar users to visualize and manipulate data in R.

Cushman, KC [ORNL] (ORCID:0000000234641151)↗

Simulation of Particulate Transport for Delivery of Solid Amendments into the Subsurface: FY24 Status Report

For particulate-based amendments to be viable for field-scale remediation at the Hanford Site (e.g., 200 DV-1 Operable Unit), particles need to be delivered a sufficient radial distance from an injection well and retained at concentrations high enough for effective treatment. An accurate description of the particle radius of influence (ROI) is critical for developing an overall remediation strategy. However, field-scale particle simulations are currently limited due to insufficient simulation capabilities and a lack of experimental data to validate and parameterize particle transport models. To help build toward field-scale deployment, this fiscal year (FY) we have (1) developed a pre screening tool to estimate particle transport, (2) implemented particle transport models within PFLOTRAN, and (3) conducted preliminary estimations of particle ROI. While field-scale numerical simulations will ultimately be necessary before remedy design and field implementation, we have developed a pre-screening tool that offers valuable estimations of expected particle injectability and ROI in a 1-D system. The advantage of the tool is that it does not require extensive laboratory experiments and instead makes predictions based solely on routine laboratory measurements. This tool can assist in down-selection and decision-making by identifying which particle amendment systems are worth pursuing in future laboratory experiments, such as 1-D column tests and beyond. With any system, scaling up from the lab to the field presents challenges. Currently, there is no field data available for model calibration or validation. However, the theoretical particle models being developed herein are the best tools available to guide progress toward field deployment. To help bridge this gap and verify model predictions, larger-scale lab experiments are being proposed. To advance simulation capabilities, six particle transport models are being integrated into the reactive transport simulator PFLOTRAN. These include colloid filtration theory (CFT) and five additional particle transport models (M1-M5). Each model, from M1 to M5, progressively incorporates additional particle transport and retention processes. Ultimately, the simplest model capable of accurately describing 1-D column data will be selected and parameterized. During FY24, the CFT and M1 model have been fully implemented within PFLOTRAN. Using an existing 1 D column experiment, the two currently implemented particle transport models (CFT and M1), and associated parameters, were fit to this experiment. While simpler model formulations are helpful for estimations, these formulations could not fully describe particle transport and retention behavior in the previous 1-D column experiment. Thus, additional complexities will need to be considered, which will be accounted for in the M2-M5 model formulations. Additionally, because a viscous, shear thinning fluid was required to keep particles in suspension, considerations for flow will also need to also be accounted for. Therefore, a new immiscible two-phase flow mode is currently being implemented in PFLOTRAN. With some modifications, this new flow module could also support simulation of non-Newtonian liquid amendments, foams, and emulsions. We also estimated the expected ROI of solid amendments using 1-D simulations. The average predicted ROI was approximately 15 ft for micron-sized zero valent iron (mZVI) suspended in xanthan gum (XG). Using the pre screening tool and ROI estimates, additional amendment-delivery laboratory characterization and experiments are proposed. The results from additional experiments can be used to validate and parametrize particulate transport model formulations, which will ultimately provide predictive capabilities for field amendment-delivery systems.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Physical, socio-psychological, and behavioural determinants of household energy consumption in the UK

Determining which attitudes and behaviours predict household energy consumption can help accelerate the low-carbon energy transition. Conventional approaches in this domain are limited, often relying on survey methods that produce data on individuals’ motivations and self-reported activities without pairing these with actual energy consumption records, which are particularly hard to collect for large, nationally representative samples. This challenge precludes the development of empirical evidence on which attitudes and behaviours influence patterns of energy consumption, thus limiting the extent to which these can inform energy interventions or conservation programs. This study demonstrates a novel methodology for estimating energy consumption in the absence of actual energy records by using a large, publicly available data set of energy consumption in the UK. We develop a predictive model using the Smart Energy Research Laboratory (SERL) data portal (with records from nearly 13,000 UK households) and then use this model to predict energy consumption (both electric and gas) for a sample of 1,000 UK householders for which we separately collect over 200 variables relating to climate change attitudes and practices. Our approach uses a set of over 50 independent variables that are shared between the data sets, allowing us to train a model on the SERL data and use it to analyse the relationship between energy consumption and the opinions, motivations, and daily practices of survey respondents. Results show that electricity consumption is influenced by a broader range of factors compared to gas. Household energy use is best explained by physical dwelling characteristics, socio-demographic variables, and certain behavioural and attitudinal measures. Notably, pro-environmental attitudes, frugality, and conscientiousness correlate with lower energy use, while income and consumerism are linked to higher consumption. We discuss how these findings can inform efforts to decarbonise home energy use in the UK.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗

Review of data-driven models for quantifying load shed by non-residential buildings in the United States

Shifting and shedding power demand in buildings can be cost-effective techniques for grids to function reliably and for end users to earn compensation. Grid operators reimburse customers in proportion to the quantity of load shed. Simple data-driven methods are used to quantify this shed, which is the difference between a measured load during the event and modeled "baseline" that would have occurred in absence of the event. These methods have evolved over the years and in many cases have been integrated with building physics, to make them a hybrid between physics based and empirical models. However, there is no comprehensive analysis that provides guidance to building operators, grid operators and researchers in selecting appropriate models based on their specific needs and available data. Here, this work aims to fill this gap by critically assessing the performance of baseline models put forward from the year 2000 through 2023. The literature reviewed includes reports generated by grid operators, reports from national laboratories and academic journal articles. The work outlines modeling features like the inputs, training period, estimation method, adjustments to fine tune the predictions and metrics to evaluate the performance. A comprehensive list of 50 models has been provided. For each model, the study explores the applicability of the model to weather sensitive buildings, variability in the building profile, timing of the event, and whether the building reduces energy consumption before an event. The work identifies the situations in which a particular model works and draws lessons based on evidence of performance. Finally, recommendations to aid in model selection are given.

97 MATHEMATICS AND COMPUTING↗

The Global Spectra-Trait Initiative: A database of paired leaf spectroscopy and functional traits associated with leaf photosynthetic capacity

Accurate assessment of leaf functional traits is crucial for a diverse range of applications from crop phenotyping to parameterizing global climate models. Leaf reflectance spectroscopy offers a promising avenue to advance ecological and agricultural research by complementing traditional, time-consuming gas exchange measurements. However, the development of robust hyperspectral models for predicting leaf photosynthetic capacity and associated traits from reflectance data has been hindered by limited data availability across species and environments. Here we introduce the Global Spectra-Trait Initiative (GSTI), a collaborative repository of paired leaf hyperspectral and gas exchange measurements from diverse ecosystems. The GSTI repository currently encompasses over 7500 observations from 397 species and 41 sites gathered from 36 published and unpublished studies, thereby offering a key resource for developing and validating hyperspectral models of leaf photosynthetic capacity. The GSTI database is developed on GitHub (https://github.com/plantphys/gsti, last access: 4 January 2026) and published to ESS-DIVE https://doi.org/10.15485/2530733, Lamour et al., 2025). It includes gas exchange data, derived photosynthetic parameters, and key leaf traits often associated with traditional gas exchange measurements such as leaf mass per area and leaf elemental composition. By providing a standardized repository for data sharing and analysis, we present a critical step towards creating hyperspectral models for predicting photosynthetic traits and associated leaf traits for terrestrial plants.

Lamour, Julien [Université of Toulouse (France); U↗

D–MOPH–25: diverse MOF–molecule pairs for Henry’s constants prediction

Computational methods like grand-canonical Monte Carlo simulations and machine learning (ML) have accelerated metal–organic frameworks (MOF) exploration but are typically limited to a narrow range of adsorbates due to data availability and force field constraints. In this study, we introduce a dataset of diverse MOF–molecule pairs for Henry’s constant prediction, D–MOPH–25, which systematically explores a diverse chemical space by combining 113 molecular adsorbates with over 5000 MOF structures through an active learning process. D–MOPH–25 constitutes the most diverse adsorbate dataset used in any ML study of molecular adsorption in MOFs to date. Our workflow builds a benchmark for predicting Henry’s constants at 300 K, leveraging conformal prediction for uncertainty quantification. Assessment through Shannon entropy and uniform manifold approximation and projection confirms the comprehensiveness of D–MOPH–25 while highlighting the importance of robust classification to filter out unphysical data points in regression tasks. Although future enhancements in model architecture and sampling criteria could improve predictive performance, our dataset already spans the target space using only 2.31% of total possibilities. This comprehensive dataset facilitates assessment of model generalizability across adsorbate species and can establish a foundation for high-throughput MOF screening and ML-driven separation processes.

active learning↗

Queued Up: 2025 Edition – Characteristics of Power Plants Seeking Transmission Interconnection As of the End of 2024 [Slides]

Electric transmission system operators (ISOs, RTOs, or utilities) require proposed power plants seeking to connect to the transmission grid to undergo a series of impact studies before they can be built. This process establishes what new transmission equipment or upgrades may be needed before a project can connect to the system and assigns the costs of that equipment. The lists of projects in this process are known as “interconnection queues”. In collaboration with interconnection.fyi, Berkeley Lab compiled, aggregated, and cleaned interconnection queue data from >50 transmission grid operators (7 ISO/RTOs and 49 non-ISO balancing areas), which collectively represent ~97% of currently installed U.S. electric generating capacity. The dataset includes requests submitted to queues through the end of 2024, and only includes requests seeking to connect to the transmission grid (not distribution-connected or behind-the-meter projects). The files below include both a PDF report and an Excel data file. The PDF report analyzes interconnection data and metrics through the end of 2024. The Excel data file includes (a) the full project-level interconnection queue dataset through 2024, (b) a codebook (data dictionary) describing each data field, and (c) 35 additional tabs featuring tables summarizing a range of interconnection metrics. Key highlights from the Queued Up: 2025 Edition (featuring data through 2024) include: • As of the end of 2024, there were ~10,300 projects actively seeking grid interconnection in the U.S., representing 1,400 GW of generation and approximately 890 GW of storage. • Historic withdrawal rates alongside relatively fewer new requests resulted in a 12% decrease in total active queue volume compared to the prior year. • Active natural gas capacity (136 GW, +72% year-over-year) increased in 2024, while solar (956 GW, -12%), storage (890 GW, -13%), and wind (271 GW, -26%) capacity decreased. • 408 GW of capacity already has a draft or executed interconnection agreement (IA) but has not yet reached commercial operations. • The time projects spend in queues before reaching COD is increasing. For the regions with available data, the median duration from IR to COD has doubled from <2 years for projects built in 2000-2007 to over 4 years for those built in 2018-2024. • Ultimately, most of this proposed capacity will not be built. Only 13% of capacity that submitted interconnection requests from 2000-2019 had reached commercial operations by the end of 2024; 77% of that capacity had been withdrawn and 10% was still active. • FERC Order 2023 and various other reforms are being implemented. These are important measures to reduce interconnection bottlenecks and enhance grid system reliability, but it is too early to measure and assess their full impact. • New additions for the 2025 edition include: (a) additional detail on data processing and gaps; (b) updates on interconnection reforms; (c) new analysis on interconnection agreements, and more.

24 POWER TRANSMISSION AND DISTRIBUTION↗

Bayesian event categorization matrix approach for explosion monitoring

Current efforts to correctly categorize natural events from suspected explosion sources with data that is collected by ground- or space-based sensors presents historical challenges that remain unaddressed by the Event Categorization Matrix (ECM) model. Smaller historical events (lower yield explosions) may have data available from fewer measurement techniques than are available today, and therefore, a historical event record can lack a complete set of discriminants. The covariance structures can also differ between such observations of event (source-type) categories. Both obstacles are problematic for the classic ECM model. Our work addresses this gap and presents a Bayesian update to the previous ECM model, termed the Bayesian Event Categorization Matrix model, which can be trained on partial observations and does not rely on a pooled covariance structure. We further augment the ECM model with Bayesian Decision Theory so that false negative or false positive rates of an event categorization can be reduced in an intuitive manner. To demonstrate improved categorization rates for the Bayesian Event Categorization Matrix model, we compare an array of Bayesian and classic models with multiple performance metrics using Monte Carlo experiments. We use both synthetic and real data. Our Bayesian models show consistent gains in overall accuracy and lower false negative rates relative to the classic ECM model. Here, we propose future avenues to improve Bayesian Event Categorization Matrix models’ decision making and predictive capability.

58 GEOSCIENCES↗

Diversity of Sordariales Fungi: Identification of Seven New Species of Naviculisporaceae Through Morphological Analyses and Genome Sequencing

Thanks to next-generation sequencing (NGS) technologies, the diversity of fungi can now be investigated through the analysis of their genome sequences. Naviculisporaceae is a family within the Sordariales, whose diversity is not well-known, with only one genome sequence published for this family. Here, we report on the isolation and cultivation of 20 new strains of Naviculisporaceae. Their genome sequences, as well as those of the five commercially available strains, were determined, thus providing complete genome sequences for 25 new Naviculisporaceae strains. Species delimitation was conducted using a combination of (1) ITS + LSU phylogenetic analysis of the new isolates along with other known species of the family, (2) comparisons between DNA barcode sequences of the new strains with those of the known species, and (3) average genome-wide nucleotide identity calculation. We built a phylogenomic tree and studied the organization of the mating-type locus. In vitro fruiting was obtained for 16 strains, enabling the definition of seven new species, namely Pseudorhypophila gallica, Pseudorhypophila guyanensis Rhypophila alpibus, Rhypophila brasiliensis, Rhypophila camarguensis, Rhypophila reunionensis and Rhypophila thailandica, as well as two new combinations, namely Pseudorhypophila latipes and Pseudorhypophila oryzae. Eight strains for which in vitro fruiting was not obtained may belong to additional new species. These results expand the known diversity of the Naviculisporaceae and greatly enlarge the genomic data available for the family.

Naviculisporaceae↗

INTEGRATION OF DATA ANALYTICS WITH SYSTEM HEALTH PROGRAMS

Industry equipment reliability and asset management programs are essential elements that help ensure the safe and economical operation of nuclear power plants. The effectiveness of these programs is addressed in several industry developed and regulatory programs. However, these programs have proven to be labor intensive and expensive. There is an opportunity to significantly enhance the collection, analysis, and use of this information to provide more cost-effective plant operation. Additionally, there is an acute industry need to leverage advanced technology to reduce costs and improve operational effectiveness. The goal of this paper is to provide effective and efficient analytical methods and tools to support risk-informed decisions for the equipment reliability and asset management programs at nuclear power plants. This is accomplished by creating a direct bridge between component health/lifecycle data and decision making (e.g., maintenance scheduling and project prioritization). Here we are supporting typical system engineer decisions regarding maintenance activity scheduling and component ageing management. This is performed in a risk-informed context where herein the term “risk” is broadly constructed to include both plant reliability and economics. This framework combines data analytics tools to analyze equipment reliability data with risk-informed methods designed to support system engineer decisions (e.g., maintenance and replacement schedules, optimal maintenance posture) in a customizable workflow. A challenge is that the structure of this workflow strongly depends on the decision that needs to be made, the type of data available, and the constraints that need to be considered. Current methods are designed to provide specific answers to specific problems; however, these methods might prove to be inadequate even when problem settings slightly change (e.g., different types of requirements, additional dependencies between system reliability and economics). We tackled this challenge by designing framework in a flexible and modular fashion such that the user can assemble and customize his/her own workflow that integrates SSC economic lifecycle models (e.g., maintenance and replacement costs), system reliability models, and optimization methods.

97 - MATHEMATICS AND COMPUTING↗

Report priority gaps in high temperature thermodynamic data (Interim Progress Report)

This interim progress report (Level 4 Milestone Number M4SF-26LL010203023) summarizes research conducted at Lawrence Livermore National Laboratory (LLNL) within the Argillite Host Rock Properties & Processes SF-26LL01020302. Our focus is to assess gaps in data availability and understanding for radionuclide thermodynamics within the context of a “hot repository” concept and expand SUPCRT-NE database development to address higher temperatures needed for a DPC DGR disposal concept. The database is intended to inform the argillite GDSA baseline model. The leading European thermochemical database (Thermochimie) is only applicable to temperatures below 80°C. Thus, a US effort to integrate and expand upon other international thermodynamics database efforts is needed, particular if a “hot repository” concept moves forward.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Utilization of Data Augmentation Techniques in Automated Inspection Systems for Defect Detection in Metals With Limited Data

Accurate identification of defects on metal surfaces is of great interest to many industry sectors, such as the automotive and aerospace industries. In contrast to conventional manual inspection techniques, recent automated inspection systems employ deep learning models trained to detect defects rapidly and precisely. The development of these models often requires a substantial image dataset to acquire adequate knowledge of defect features and enhance their predictive accuracy. When data is limited, augmentation techniques are often used to improve the precision and accuracy of defect detection systems. This study examined the prediction performance of two object detection models, namely Faster Region‐based Convolutional Neural Network (Faster R‐CNN) and You Only Look Once version 8 (YOLOv8), to identify dent defects in limited images of cast iron cylinder head surfaces. The original image set contains 46 images with 563 dents. To overcome limited data availability, common image augmentation techniques along with a copy‐paste method were applied. Results show that standard augmentation improved YOLOv8 accuracy by 8.00% and average precision (AP) by 3.00%. On the other hand, the copy‐paste technique achieved a 20.00% increase in accuracy and a 1% increase in AP with just 200 synthetic dents. Furthermore, these results provide support for using the copy‐paste augmentation strategy to enhance defect detection performance, with a limited dataset, contributing to more accurate defect identification in remanufacturing processes.

36 MATERIALS SCIENCE↗

On the intermediate Jacobian of M5-branes

Abstract We study Euclidean M5-branes wrapping vertical divisors in elliptic Calabi-Yau fourfold compactifications of M/F-theory that admit a Sen limit. We construct these Calabi-Yau fourfolds as elliptic fibrations over coordinate flip O3/O7 orientifolds of toric hypersurface Calabi-Yau threefolds. We devise a method to analyze the Hodge structure (and hence the dimension of the intermediate Jacobian) of vertical divisors in these fourfolds, using only the data available from a type IIB compactification on the O3/O7 Calabi-Yau orientifold. Our method utilizes simple combinatorial formulae (that we prove) for the equivariant Hodge numbers of the Calabi-Yau orientifolds and their prime toric divisors, along with a formula for the Euler characteristic of vertical divisors in the corresponding elliptic Calabi-Yau fourfold. Our formula for the Euler characteristic includes a conjectured correction term that accounts for the contributions of pointlike terminal ℤ 2 singularities corresponding to perturbative O3-planes. We check our conjecture in a number of explicit examples and find perfect agreement with the results of direct computations.

Physics↗

Increased inflammation as well as decreased endoplasmic reticulum stress and translation differentiate pancreatic islets from donors with pre-symptomatic stage 1 type 1 diabetes and non-diabetic donors

Aims/hypothesis Progression to type 1 diabetes is associated with genetic factors, the presence of autoantibodies and a decline in beta cell insulin secretion in response to glucose. Very little is known regarding the molecular changes that occur in human insulin-secreting beta cells prior to the onset of type 1 diabetes. Herein, we applied an unbiased proteomics approach to identify changes in proteins and potential mechanisms of islet dysfunction in islet-autoantibody-positive organ donors with pre-symptomatic stage 1 type 1 diabetes (HbA1c ≤42 mmol/mol [6.0%]). We aimed to identify pathways in islets that are indicative of beta cell dysfunction. Methods Multiple islet sections were collected through laser microdissection of frozen pancreatic tissues from organ donors positive for single or multiple islet autoantibodies (AAb + , n=5), and age (±2 years)- and sex-matched non-diabetic (ND) control donors (n=5) obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD). Islet sections were subjected to MS-based proteomics and analysed with label-free quantification followed by pathway and functional annotations. Results Analyses resulted in ~4500 proteins identified with low false discovery rate (<1%), with 2165 proteins reliably quantified in every islet sample. We observed large inter-donor variations that presented a challenge for statistical analysis of proteome changes between donor groups. We therefore focused on only the donors with stage 1 type 1 diabetes who were positive for multiple autoantibodies (mAAb + , n=3) and genetic risk compared with their matched ND controls (n=3) for the final statistical analysis. Approximately 10% of the proteins (n=202) were significantly different (unadjusted p<0.025, q<0.15) for mAAb + vs ND donor islets. The significant alterations clustered around major functions for upregulation in the immune response and glycolysis, and downregulation in endoplasmic reticulum (ER) stress response as well as protein translation and synthesis. The observed proteome changes were further supported by several independent published datasets, including a proteomics dataset from in vitro proinflammatory cytokine-treated human islets and single-cell RNA-seq datasets from AAb + individuals. Conclusions/interpretation In situ human islet proteome alterations in stage 1 type 1 diabetes centred around several major functional categories, including an expected increase in immune response genes (elevated antigen presentation/HLA), with decreases in protein synthesis and ER stress response, as well as compensatory metabolic response. The dataset serves as a proteomics resource for future studies on beta cell changes during type 1 diabetes progression and pathogenesis. Data availability The LC-MS raw datasets that support the findings of this study have been deposited in the online repository: MassIVE (https://massive.ucsd.edu/ProteoSAFe/static/massive.jsp) with accession no. MSV000090212.

Autoantibody-positive↗