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Decoding the effects of synonymous variants

Synonymous single nucleotide variants (sSNVs) are common in the human genome but are often overlooked. However, sSNVs can have significant biological impact and may lead to disease. Existing computational methods for evaluating the effect of sSNVs suffer from the lack of gold-standard training/evaluation data and exhibit over-reliance on sequence conservation signals. We developed synVep (synonymous Variant effect predictor), a machine learning-based method that overcomes both of these limitations. Our training data was a combination of variants reported by gnomAD (observed) and those unreported, but possible in the human genome (generated). We used positive-unlabeled learning to purify the generated variant set of any likely unobservable variants. We then trained two sequential extreme gradient boosting models to identify subsets of the remaining variants putatively enriched and depleted in effect. Our method attained 90% precision/recall on a previously unseen set of variants. Furthermore, although synVep does not explicitly use conservation, its scores correlated with evolutionary distances between orthologs in cross-species variation analysis. synVep was also able to differentiate pathogenic vs. benign variants, as well as splice-site disrupting variants (SDV) vs. non-SDVs. Thus, synVep provides an important improvement in annotation of sSNVs, allowing users to focus on variants that most likely harbor effects.

Zishuo Zeng↗

Guidance and Control Software Project Data - Volume 1: Planning Documents

The Guidance and Control Software (GCS) project was the last in a series of software reliability studies conducted at Langley Research Center between 1977 and 1994. The technical results of the GCS project were recorded after the experiment was completed. Some of the support documentation produced as part of the experiment, however, is serving an unexpected role far beyond its original project context. Some of the software used as part of the GCS project was developed to conform to the RTCA/DO-178B software standard, "Software Considerations in Airborne Systems and Equipment Certification," used in the civil aviation industry. That standard requires extensive documentation throughout the software development life cycle, including plans, software requirements, design and source code, verification cases and results, and configuration management and quality control data. The project documentation that includes this information is open for public scrutiny without the legal or safety implications associated with comparable data from an avionics manufacturer. This public availability has afforded an opportunity to use the GCS project documents for DO-178B training. This report provides a brief overview of the GCS project, describes the 4-volume set of documents and the role they are playing in training, and includes the planning documents from the GCS project. Volume 1 contains five appendices: A. Plan for Software Aspects of Certification for the Guidance and Control Software Project; B. Software Development Standards for the Guidance and Control Software Project; C. Software Verification Plan for the Guidance and Control Software Project; D. Software Configuration Management Plan for the Guidance and Control Software Project; and E. Software Quality Assurance Activities.

Hayhurst, Kelly J.↗

A comprehensive spectral assay library to quantify the Halobacterium salinarum NRC-1 proteome by DIA/SWATH-MS

Data-Independent Acquisition (DIA) is a mass spectrometry-based method to reliably identify and reproducibly quantify large fractions of a target proteome. The peptide-centric data analysis strategy employed in DIA requires a priori generated spectral assay libraries. Such assay libraries allow to extract quantitative data in a targeted approach and have been generated for human, mouse, zebrafish, E. coli and few other organisms. However, a spectral assay library for the extreme halophilic archaeon Halobacterium salinarum NRC-1, a model organism that contributed to several notable discoveries, is not publicly available yet. Here, we report a comprehensive spectral assay library to measure 2,563 of 2,646 annotated H. salinarum NRC-1 proteins. We demonstrate the utility of this library by measuring global protein abundances over time under standard growth conditions. The H. salinarum NRC-1 library includes 21,074 distinct peptides representing 97% of the predicted proteome and provides a new, valuable resource to confidently measure and quantify any protein of this archaeon. Data and spectral assay libraries are available via ProteomeXchange (PXD042770, PXD042774) and SWATHAtlas (SAL00312-SAL00319).

59 BASIC BIOLOGICAL SCIENCES↗

Considerations regarding the Use of Computer Vision Machine Learning in Safety-Related or Risk-Significant Applications in Nuclear Power Plants

With the advancements made to date in the field of artificial intelligence (AI), significant potential exists to utilize AI capabilities for nuclear power plant (NPP) applications. AI can replicate human decision making and it is usually faster and more accurate than humans. For implementations that impact critical NPP applications (e.g., safety-related or non-safety systems that potentially affect overall plant risk), a deeper safety analysis of the AI methods is necessary. AI applied to NPP operations could resemble the use of digital I&C (DI&C) because such applications involve digital computer hardware and custom-designed software that input plant data, execute complex software algorithms, and output the results to a system or licensed human operator to potentially provoke an action. For AI methods to be compliant with current safety requirements for DI&C, AI compatibility must be evaluated, and AI-related gaps may exist that prevent the prompt deployment of AI in NPPs. This effort aims to evaluate how example AI technologies align with the DI&C safety framework, and discusses how they could be analyzed, modeled, tested, and validated in a manner similar to typical DI&C technologies. Because AI is a broad field that encompasses areas such as machine learning (ML), natural language processing, and computer vision, this research focused on a subset of methods categorized as the computer vision ML (CVML) methods. This report explores two CVML use cases, gauge reading and fire watch, considered relevant to the DI&C standards, as they could play a safety-critical role. For the gauge reading use case, a CVML-enabled technology that can read gauges at oblique angles is utilized. For the fire watch use case, a CVML-enabled technology is utilized that migrates fire watch from a manual (human) approach to automated fire detection. These use cases are mainly intended to give context to the CVML system discussion. This effort assumes the worst-case scenario, with the CVML system being used to replace a safety-related or risk-significant system, thus requiring evaluation. Evaluating CVML against most of the relevant safety requirements for DI&C yielded several CVML-specific considerations due to the uniqueness of its characteristics in comparison with typical DI&C systems. For example, CVML models often employ commonly used (open-source) datasets, and it is not always possible to determine the level of overlap among open-source datasets. Therefore, the independence of the developed CVML models when demonstrating diversity is questionable, therefore creating vulnerability to common cause failure (CCF). The design verification process is also impacted since the data overlap could result in overestimation of the software validation and verification (V&V) performance results. Section 2 of this report evaluates a list of the identified CVML-specific characteristics and discusses the resulting considerations and potential solutions in the context of each referenced requirement. A summation is provided in Section 3. This report is not to be used as a guideline. It was developed to identify and consider issues in the implementation of ML technologies used to augment activities that may have a bearing on plant operation. The report draws parallels to the use of DI&C technologies, for which many standards are available to guide their use in nuclear plant operation. It considers the technologies and some of the potential implications of their use in safety-related applications but is not intended to address regulatory or licensing related issues.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Princeton Plasma Physics Laboratory Annual Site Environmental Report for Calendar Year 2024

This report provides the US Department of Energy (DOE) and the public with information on the level of radioactive and non-radioactive pollutants (if any) that are added to the environment as a result of Princeton Plasma Physics Laboratory’s (PPPL) operations. This report fulfills the annual public reporting requirements of DOE Order 231.1B. The results of PPPL’s 2024 environmental surveillance and monitoring program are presented and discussed. The report also summarizes environmental initiatives, assessments, and community involvement programs that were undertaken in 2024. PPPL has engaged in fusion energy research since 1951 and at its current locations since 1958. The Laboratory’s mission is to develop the scientific knowledge and advanced engineering to enable fusion to power the US and the world, and to develop the understanding of plasmas from the nano- to the astrophysical scale. PPPL’s primary experiment, the National Spherical Torus Experiment-Upgrade (NSTX-U) is a collaboration among national laboratories, universities, and national and international research institutions and is a major element in the US Fusion Energy Sciences Program. Its design tests the physics principles of spherical torus (ST) plasmas, playing an important role in the development of smaller, more economical fusion reactors. Due to previous operational issues, NSTX-U did not operate in 2024. PPPL is engaged in a project to replace key NSTX-U components and systems to enable the operation of this international magnetic fusion user facility. In 2024, PPPL’s radiological environmental monitoring program measured tritium in the air at onsite sampling stations. Using highly sensitive air monitors, PPPL is capable of detecting small changes in the ambient levels of tritium. The operation of monitors located on D-site is used to demonstrate compliance with the National Emission Standard for Hazardous Air Pollutants (NESHAPs) regulations. Also included in PPPL’s radiological environmental monitoring program, are water monitoring – ground, surface, and waste waters. PPPL’s radiological monitoring program characterized the background levels of tritium in the environment and those data are presented in this report. Ground water monitoring continued under New Jersey Department of Environmental Protection’s (NJDEP) Site Remediation Program regulations. PPPL monitored for nonradiological contaminants, mainly volatile organic compounds (components of common degreasing solvents). In 2024, PPPL complied with permit limits for surface water and sanitary wastewater discharges. PPPL was honored with an award for EPEAT-certified electronics purchasing from the Global Electronics Council on July 25, 2024.

54 ENVIRONMENTAL SCIENCES↗

Increasing the Operational Value of Event Messages

Assessing the health of a space mission has traditionally been performed using telemetry analysis tools. Parameter values are compared to known operational limits and are plotted over various time periods. This presentation begins with the notion that there is an incredible amount of untapped information contained within the mission s event message logs. Through creative advancements in message handling tools, the event message logs can be used to better assess spacecraft and ground system status and to highlight and report on conditions not readily apparent when messages are evaluated one-at-a-time during a real-time pass. Work in this area is being funded as part of a larger NASA effort at the Goddard Space Flight Center to create component-based, middleware-based, standards-based general purpose ground system architecture referred to as GMSEC - the GSFC Mission Services Evolution Center. The new capabilities and operational concepts for event display, event data analyses and data mining are being developed by Lockheed Martin and the new subsystem has been named GREAT - the GMSEC Reusable Event Analysis Toolkit. Planned for use on existing and future missions, GREAT has the potential to increase operational efficiency in areas of problem detection and analysis, general status reporting, and real-time situational awareness.

Li, Zhenping↗

Search for dark matter in events with missing transverse momentum and a Higgs boson decaying into two photons in pp collisions at $$ \sqrt{s} $$ = 13 TeV with the ATLAS detector

A search for dark-matter particles in events with large missing transverse momentum and a Higgs boson candidate decaying into two photons is reported. The search uses 139 fb - 1 of proton-proton collision data collected at $$ \sqrt{s} $$ s = 13 TeV with the ATLAS detector at the CERN LHC between 2015 and 2018. No significant excess of events over the Standard Model predictions is observed. The results are interpreted by extracting limits on three simplified models that include either vector or pseudoscalar mediators and predict a final state with a pair of dark-matter candidates and a Higgs boson decaying into two photons.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

mzapy : An Open-Source Python Library Enabling Efficient Extraction and Processing of Ion Mobility Spectrometry-Mass Spectrometry Data in the MZA File Format

We have recently reported MZA, a new and simple mass spectrometry data structure based on the broadly supported HDF5 format and created to facilitate software development. While this format is inherently supportive of application development, the availability of a core library with standard mass spectrometry utilities greatly facilitates fast software development. Here, we present a Python library, mzapy, for efficient extraction and processing of mass spectrometry data in the MZA format. In addition to raw data extraction, mzapy contains supporting utilities enabling tasks including calibration, signal processing, peak finding, and generating plots. Being implemented in pure Python with minimal and largely standardized dependencies makes mzapy uniquely suited to application development in the multi-omics domain. The free and open source mzapy is built with extensibility in mind, and future development will support cloud computing and artificial intelligence/machine learning applications. The software source code is freely available at https://github.com/PNNL-m-q/mzapy.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Equilibrated Gas and Carbonate Standard‐Derived Dual (Δ 47 and Δ 48 ) Clumped Isotope Values

Abstract Carbonate clumped isotope geochemistry has primarily focused on mass spectrometric determination of m/z 47 CO 2 for geothermometry, but theoretical calculations and recent experiments indicate paired analysis of the m/z 47 ( 13 C 18 O 16 O) and m/z 48 ( 12 C 18 O 18 O) isotopologues (referred to as Δ 47 and Δ 48 ) can be used to study non‐equilibrium isotope fractionations and refine temperature estimates. We utilize 5,448 Δ 47 and 3,400 Δ 48 replicate measurements of carbonate samples and standards, and 183 Δ 47 and 195 Δ 48 replicate measurements of gas standards from 2015 to 2021 from a multi‐year and multi‐instrument data set to constrain Δ 47 and Δ 48 values for 27 samples and standards, including Devils Hole cave calcite, and study equilibrium Δ 47 ‐Δ 48 , Δ 47 ‐temperature, and Δ 48 ‐temperature relationships. We compare results to previously published findings and calculate equilibrium regressions based on data from multiple laboratories. We report acid digestion fractionation factors, Δ* 63‐47 and Δ* 64‐48 , and account for their dependence on the initial clumped isotope values of the mineral.

58 GEOSCIENCES↗

Measurement of lepton universality parameters in B + → K + ℓ + ℓ – and B 0 → K* 0 ℓ + ℓ – decays

A simultaneous analysis of the B + → K + ℓ + ℓ – and B 0 → K* 0 ℓ + ℓ – decays is performed to test muon-electron universality in two ranges of the square of the dilepton invariant mass, q 2 . The measurement uses a sample of beauty meson decays produced in proton-proton collisions collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of 9 fb –1 . A sequence of multivariate selections and strict particle identification requirements produce a higher signal purity and a better statistical sensitivity per unit luminosity than previous LHCb lepton universality tests using the same decay modes. Residual backgrounds due to misidentified hadronic decays are studied using data and included in the fit model. Each of the four lepton universality measurements reported is either the first in the given q 2 interval or supersedes previous LHCb measurements. The results are compatible with the predictions of the Standard Model.

79 ASTRONOMY AND ASTROPHYSICS↗

Leaf gas exchange data, Nov 2018 and May 2019, Daintree Rainforest, Australia

This data package contains leaf gas exchange data for 11 canopy tree species in the control and drought treatments at the Daintree Rainforest Observatory in Queensland, Australia (AU-DRO) with the purpose of testing for differences in gas exchange between treatments. Data were collected at the end of the dry season (November 2018) and end of the wet season (May 2019). Using a canopy crane, large branches (>1 m) were collected from the top of the canopy and immediately placed in a bucket of water, upon which the LI-6800 leaf chamber was clamped onto a recently mature leaf with minimal herbivory. Measurements were recorded every 3 seconds for 3 minutes total. The species included in the dataset are: Castanospermum australe, Cleistanthus myrianthus, Cryptocarya mackinnoniana, Dysoxylum papuanum, Elaeocarpus angustifolius (Elaeocarpus grandis), Endiandra microneura, Mallotus paniculatus, Myristica globosa, Rockinghamia angustifolia, Synima cordierorum, Syzygium spp. The two data files included are: 1. LICOR_Data_AU_DRO_2019_GasEx.csv (a compilation of individual LICOR output files, with correction of user input errors such as incorrect species spelling) 2. ESS_DIVE_Data_AU_DRO_2019_GasEx.csv (selected variables and converted units from LICOR_Data_AU_DRO_2019_GasEx.csv to follow the standard gas exchange reporting format from Ely et al. 2021 Ecological Informatics). The metadata files included are: (3) ESS_DIVE_Metadata_AU_DRO_2019_GasEx.xlsx (4) File_Submission_Metadata_AU_DRP_2019_GasEx.xlsx (5) E-Field_Log_AU_DRO_2019_GasEx.xlsx (6) Data_Column_Description_AU_DRO_2019_GasEx.xlsx.

54 ENVIRONMENTAL SCIENCES↗

Resilience Metrics for Solar Photovoltaics

This workshop presentation proposes the development of solar photovoltaic (PV) system resilience metrics and a methodology and framework for evaluation of PV resilience metrics. PV resilience metrics are needed to establish a consistent basis for reporting, evaluation, and data collection by industry, evaluate performance of PV systems that have been subject to natural hazards, correlating resilience to system attributes, and predicting resilience for any PV system. PV resilience metrics can guide improved system design, standards, and insurance coverage. Establishing consistent metrics can foster data collection on impacts of natural hazards on PV systems.

14 SOLAR ENERGY↗

Development of automated electromagnetic compatibility test facilities at Marshall Space Flight Center

The efforts to automate the electromagentic compatibility (EMC) test facilites at Marshall Flight Center were examined. A battery of nine standard tests is to be integrated by means of a desktop computer-controller in order to provide near real-time data assessment, store the data acquired during testing on flexible disk, and provide computer production of the certification report.

Harrison, Cecil A.↗

The FAA satellite communications program

The Federal Aviation Administration is developing satellite communications capabilities to enhance air traffic services, first in oceanic and remote regions, and later for United States domestic services. The program includes four projects which develop technical standards, assure adequate system performance, support implementation, and provide for research and development for selected areas of U.S. domestic satellite communications. The continuing focus is the application of automated data communications, which is already permitting enhanced and regular position reporting. Voice developments, necessary for non-routine communications, are also included among the necessary activities to improve ATC communications.

Burcham, Karen L.↗

Initial exploration of the ASRS database

We applied a standard classification algorithm to a subset of NASA/FAA Aviation Safety Reporting System (ASRS) database. The subset concerned incidents of aircraft altitude deviations. We are exploring the database to address questions such as: Are there 'natural' classes into which the data will fall? How would these classes correspond to recognizable events or situations? Beyond addressing these we want the data to determine directions for further study. We conducted experiments on different data subsections and analyzed diagnostics such as 'message length reduction'; these characterize the classification in terms of its significance and information content. The classification effort was successful in revealing relationships in the data that were in consonance with other studies of the data and expert opinion.

Kraft, Richard↗

2021 Annual Site Environmental Report

This report provides the U.S. Department of Energy (DOE) and the public with information on the level of radioactive and non-radioactive pollutants (if any) that are added to the environment as a result of Princeton Plasma Physics Laboratory’s (PPPL) operations. The results of PPPL’s 2021 environmental surveillance and monitoring program are presented and discussed. The report also summarizes environmental initiatives, assessments, and community involvement programs that were undertaken in 2021. PPPL’s on-site operations were significantly curtailed in 2021 due to the global coronavirus pandemic. PPPL has engaged in fusion energy research since 1951. The Laboratory’s mission is to develop the scientific knowledge and advanced engineering to enable fusion to power the U.S. and the world, and to developing the understanding of plasmas from the nano- to the astrophysical scale. PPPL’s primary experiment, the National Spherical Torus Experiment-Upgrade (NSTX-U) is a collaboration among national laboratories, universities, and national and international research institutions and is a major element in the US Fusion Energy Sciences Program. Its design tests the physics principles of spherical torus (ST) plasmas, playing an important role in the development of smaller, more economical fusion reactors. Due to previous operational issues, NSTX-U did not operate in 2021. PPPL is engaged in a project to replace key NSTX-U components and systems to enable operation of this international fusion user facility. In 2021, PPPL’s radiological environmental monitoring program measured tritium in the air at the NSTX-U Stack and at onsite sampling stations. Using highly sensitive air monitors, PPPL is capable of detecting small changes in the ambient levels of tritium. The operation of an in-stack monitor located on D-site is used to demonstrate compliance with the National Emission Standard for Hazardous Air Pollutants (NESHAPs) regulations. Also included in PPPL’s radiological environmental monitoring program, are water monitoring – ground, surface, and waste waters. PPPL’s radiological monitoring program characterized the background levels of tritium in the environment and those data are presented in this report. Ground water monitoring continued under New Jersey Department of Environmental Protection’s (NJDEP) Site Remediation Program regulations. PPPL monitored for non-radiological contaminants, mainly volatile organic compounds (components of common degreasing solvents). In 2021, PPPL complied with permit limits for surface and sanitary discharges. PPPL was honored with awards for EPEAT-certified electronics purchasing and use of peracetic acid as an alternative water treatment chemical in its non-potable process water systems an NJDEP recycling award.

54 ENVIRONMENTAL SCIENCES↗

2022 Annual Site Environment Report, Princeton Plasma Physics Laboratory

This report provides the U.S. Department of Energy (DOE) and the public with information on the level of radioactive and non-radioactive pollutants (if any) that are added to the environment as a result of Princeton Plasma Physics Laboratory’s (PPPL) operations. This report fulfills the annual public reporting requirements of DOE Order 231.1B. The results of PPPL’s 2022 environmental surveillance and monitoring program are presented and discussed. The report also summarizes environmental initiatives, assessments, and community involvement programs that were undertaken in 2022. PPPL’s on-site operations started to be restored in 2022, following curtailments in 2020 and 2021 for the global coronavirus (COVID-19) pandemic. PPPL has engaged in fusion energy research since 1951 and at its current locations since 1958. The Laboratory’s mission is to develop the scientific knowledge and advanced engineering to enable fusion to power the U.S. and the world, and to develop the understanding of plasmas from the nano- to the astrophysical scale. PPPL’s primary experiment, the National Spherical Torus Experiment-Upgrade (NSTX-U) is a collaboration among national laboratories, universities, and national and international research institutions and is a major element in the US Fusion Energy Sciences Program. Its design tests the physics principles of spherical torus (ST) plasmas, playing an important role in the development of smaller, more economical fusion reactors. Due to previous operational issues, NSTX-U did not operate in 2022. PPPL is engaged in a project to replace key NSTX-U components and systems to enable the operation of this international magnetic fusion user facility. In 2022, PPPL’s radiological environmental monitoring program measured tritium in the air at onsite sampling stations. Using highly sensitive air monitors, PPPL is capable of detecting small changes in the ambient levels of tritium. The operation of monitors located on D-site is used to demonstrate compliance with the National Emission Standard for Hazardous Air Pollutants (NESHAPs) regulations. Also included in PPPL’s radiological environmental monitoring program, are water monitoring – ground, surface, and waste waters. PPPL’s radiological monitoring program characterized the background levels of tritium in the environment and those data are presented in this report. Ground water monitoring continued under New Jersey Department of Environmental Protection’s (NJDEP) Site Remediation Program regulations. PPPL monitored for non-radiological contaminants, mainly volatile organic compounds (components of common degreasing solvents). In 2022, PPPL complied with permit limits for surface water and sanitary wastewater discharges. PPPL was honored with an award for EPEAT-certified electronics purchasing from the Global Electronics Council.

54 ENVIRONMENTAL SCIENCES↗

Measurement of the muon anomalous precession frequency in runs 2 \& 3 of the Muon $g-2$ Experiment at Fermilab

This dissertation presents a measurement of the muon anomalous precession frequency for the Runs 2 \& 3 data of the E989 Muon $g-2$ Experiment at Fermilab. The muon anomalous precession frequency is one of two key inputs, the other being the magnetic field, used to precisely determine the muon magnetic anomaly, $a_{\mu}$. In April 2021, the E989 collaboration reported its first measurement of $a_{\mu}$ to an unprecedented precision of 460 parts-per-billion (ppb). This result is in agreement with the previous measurement performed by the E821 collaboration at Brookhaven National Laboratory, and the combined experimental value is in tension with the Standard Model prediction at 4.2$\sigma$, a possible hint of new physics. The first result from E989 was based on the Run-1 data, which was collected in 2018 and comprises 6\% of the experiment’s target statistics; the Run-1 result was statistics-limited. The Runs 2 \& 3 data were collected in 2019-2020 and constitute a four-fold increase i n statistics compared to Run-1 and consequently, a factor of two reduction in the measurement’s statistical uncertainty. This reduced statistical uncertainty, as well as continued understanding of systematic effects, will result in an even more precise measurement of $a_{\mu}$ and will help clarify the observed tension between theory and experiment. The precession frequency analysis presented in this dissertation includes a number of improvements compared to Boston University's Run-1 analysis: the implementation of a more robust pileup-subtraction procedure, the implementation of a kernel ratio method, the adoption of the statistically optimal asymmetry-weighted method, and investigations that led to an improved understanding of an outstanding residual slow effect. This dissertation motivates a measurement of the muon magnetic anomaly, describes the experimental principle, gives an overview of the E989 experiment, and presents a precession frequency analysis with full systematic unc ertainty evaluation for the Runs 2 \& 3 data. The combined precession frequency measurement, using the ratio asymmetry-weighted method, has a statistical uncertainty of 201 ppb and a systematic uncertainty of 25 ppb, constituting the most precise determination of the muon anomalous precision frequency to date.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗