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DOE OSTI2017

Precancer Atlas to Drive Precision Prevention Trials

Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. Here, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity – basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. In conclusion, accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA – an immense national resource to interrogate, target, and intercept events that drive oncogenesis.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL

Activated B cell–like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11–BCL10–MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Visual inspection reliability for precision manufactured parts

Sandia National Laboratories conducted an experiment for the National Nuclear Security Administration to determine the reliability of visual inspection of precision manufactured parts used in nuclear weapons. In addition visual inspection has been extensively researched since the early 20th century; however, the reliability of visual inspection for nuclear weapons parts has not been addressed. In addition, the efficacy of using inspector confidence ratings to guide multiple inspections in an effort to improve overall performance accuracy is unknown. Further, the workload associated with inspection has not been documented, and newer measures of stress have not been applied.

98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL P↗

DOE OSTI2024

Numerical eigen-spectrum slicing, accurate orthogonal eigen-basis, and mixed-precision eigenvalue refinement using OpenMP data-dependent tasks and accelerator offload

Performing a variety of numerical computations efficiently and, at the same time, in a portable fashion requires both an overarching design followed by a number of implementation strategies. All of these are exemplified below as we present transitioning the PLASMA numerical library from relying on dependence-driven large tasks to achieving utilization of fine grain tasking and offload to hardware accelerators while keeping its core dependence sets: OpenMP source code pragmas and runtime for most system-level functionality and basic low-level numerical kernels provided directly by hardware vendors or open source projects with vendor contributions. We also present new algorithmic methods and their efficient parallel implementations including fine grained tasking for eigen-spectrum slicing and offload for mixed-precision eigenvalue refinement. We provide performance, scaling, and numerical results showing sizable gains over the available solutions from either the open source and vendor-provided packages.

Luszczek, Piotr↗

DOE OSTI2024

Improving precision and accuracy of genetic mapping with genotyping-by-sequencing data in outcrossing species

This dataset contains all data and supplementary materials from "Improving precision and accuracy of genetic mapping with genotyping-by-sequencing data in outcrossing species". An Excel file a list of all QTLs and linkage group length (in cM) obtained with two different SNP-calling methods (Tassel-Uneak and Tassel-GBS), genetic map-construction method (linkage-only and reference order-corrected) and depth filters (12x, 20x, 30x and 40x) for genetic mapping of 18 biomass yield traits in a biparental Miscanthus sinensis population using RAD-Seq SNPs is provided as "Supplementary file 1". A Perl script with the code for filtering VCF and HapMap-formatted data files is provided as “Supplementary file 2”. Phenotype data used for QTL mapping is provided as “Supplementary File 3”. A Perl script with the code for the simulation study is provided as “Supplementary file 4”.

GenotypingSimulator↗

DOE OSTI2022

Precise 3D reactor core calculation using spherical harmonics and discontinuous Galerkin finite element methods

We study the use of P{sub N} method in angle and discontinuous Galerkin is space to solve 3D neutron transport problem. P{sub N} method consists in developing the angular flux on truncated spherical harmonics basic. In this paper, we couple this method with the discontinuous finite elements in space to obtain a complete discretization of the multigroup neutron transport equation. To investigate its precision, the method was applied to Takeda and C5G7 benchmark problems. These calculations point out that the proposed P{sub N}-DG method is capable of producing accurate solutions in small computational time, and that it is able to handle complex 3D geometries. (authors)

22 GENERAL STUDIES OF NUCLEAR REACTORS↗

DOE OSTI2022

Increased phase precision of spatial light modulators using irrational slopes: application to attosecond metrology

The ability of spatial light modulators (SLMs) to modify the amplitude and phase of light has proved them invaluable to the optics and photonics community. In many applications, the bit-depth of SLMs is a major limiting factor dictated by a digital processor. As a result, there is usually a compromise between refresh speed and bit-depth. Here, we present a method to increase the effective bit-depth of SLMs, which utilizes a linear slope, as is commonly applied to deal with the zeroth-order effect. This technique was tested using two interferometric transient absorption spectroscopy setups. Through the high harmonic generation in gases producing a train of attosecond pulses and harmonics from solids in the ultraviolet, two pulses are generated that interfere in the far field providing a measurement of the optical phase. An increase in the precision far beyond the limit dictated by the digital processor in the bit-depth was found.

Harrison, Geoffrey R. (ORCID:0000000152141866)↗

DOE OSTI2011

High-precision diode-laser-based temperature measurement for air refractive index compensation

We present a laser-based system to measure the refractive index of air over a long path length. In optical distance measurements, it is essential to know the refractive index of air with high accuracy. Commonly, the refractive index of air is calculated from the properties of the ambient air using either Ciddor or Edlen equations, where the dominant uncertainty component is in most cases the air temperature. The method developed in this work utilizes direct absorption spectroscopy of oxygen to measure the average temperature of air and of water vapor to measure relative humidity. The method allows measurement of temperature and humidity over the same beam path as in optical distance measurement, providing spatially well-matching data. Indoor and outdoor measurements demonstrate the effectiveness of the method. In particular, we demonstrate an effective compensation of the refractive index of air in an interferometric length measurement at a time-variant and spatially nonhomogeneous temperature over a long time period. Further, we were able to demonstrate 7 mK RMS noise over a 67 m path length using a 120 s sample time. To our knowledge, this is the best temperature precision reported for a spectroscopic temperature measurement.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

DOE OSTI2021

Milliradian precision ultrafast pulse control for spectral phase metrology

A pulse-shaper-based method for spectral phase measurement and compression with milliradian precision is proposed and tested experimentally. Measurements of chirp and third-order dispersion are performed and compared to theoretical predictions. The single-digit milliradian accuracy is benchmarked by a group velocity dispersion measurement of fused silica.

Stamm, Jacob↗

DOE OSTI2023

Towards quantum telescopes: demonstration of a two-photon interferometer for precision astrometry

Classical optical interferometry requires maintaining live, phase-stable links between telescope stations. This requirement greatly adds to the cost of extending to long baseline separations and limits on baselines will in turn limit the achievable angular resolution. Here we describe a novel type of two-photon interferometer for astrometry, which uses photons from two separate sky sources and does not require an optical link between stations. Such techniques may make large increases in interferometric baselines practical, even by orders of magnitude, with a corresponding improvement in astrometric precision benefiting numerous fields in astrophysics. We tested a benchtop analogue version of the two-source interferometer and unambiguously observe correlated behavior in detections of photon pairs from two thermal light sources, in agreement with theoretical predictions. This work opens new possibilities in future astronomical measurements.

47 OTHER INSTRUMENTATION↗

DOE OSTI2022

Controlled precision QUBO-based algorithm to compute eigenvectors of symmetric matrices

We describe an algorithm to compute the extremal eigenvalues and corresponding eigenvectors of a symmetric matrix which is based on solving a sequence of Quadratic Binary Optimization problems. This algorithm is robust across many different classes of symmetric matrices; It can compute the eigenvector/eigenvalue pair to essentially any arbitrary precision, and with minor modifications, can also solve the generalized eigenvalue problem. Performance is analyzed on small random matrices and selected larger matrices from practical applications.

97 MATHEMATICS AND COMPUTING↗

DOE OSTI2015

Precise Relative Earthquake Magnitudes from Cross Correlation

We present a method to estimate precise relative magnitudes using cross correlation of seismic waveforms. Our method incorporates the intercorrelation of all events in a group of earthquakes, as opposed to individual event pairings relative to a reference event. This method works well when a reliable reference event does not exist. We illustrate the method using vertical strike-slip earthquakes located in the northeast Pacific and Panama fracture zone regions. Our results are generally consistent with the Global Centroid Moment Tensor catalog, which we use to establish a baseline for the relative event sizes.

58 GEOSCIENCES↗

DOE OSTI2016

Muon Beam Tracking and Spin-Orbit Correlations for Precision g-2 Measurements

The main goal of the Muon g-2 Experiment (g-2) at Fermilab is to measure the muon anomalous magnetic moment to unprecedented precision. This new measurement will allow to test the completeness of the Standard Model (SM) and to validate other theoretical models beyond the SM. The close interplay of the understanding of particle beam dynamics and the preparation of the beam properties with the experimental measurement is tantamount to the reduction of systematic errors in the determination of the muon anomalous magnetic moment. We describe progress in developing detailed calculations and modeling of the muon beam delivery system in order to obtain a better understanding of spin-orbit correlations, nonlinearities, and more realistic aspects that contribute to the systematic errors of the g-2 measurement. Our simulation is meant to provide statistical studies of error effects and quick analyses of running conditions for when g-2 is taking beam, among others. We are using COSY, a differential algebra solver developed at Michigan State University that will also serve as an alternative to compare results obtained by other simulation teams of the g-2 Collaboration.

43 PARTICLE ACCELERATORS↗

DOE OSTI2019

Muon g-2: An Interplay between Beam Dynamics and a Muon Decay Experiment at the Precision Frontier

The Muon g-2 Experiment at Fermilab (E989) will use the higher proton flux delivered by the Fermilab accelerator complex and improvements to the experimental apparatus to measure the anomalous magnetic moment of the muon to unprecedented precision. In addition to the increased statistics beyond the most recent measurement, the experiment relies on detailed understanding of the beam dynamics in the experiment’s storage ring as well as the incoming muon beam properties for proper assessments of systematic errors in the data analysis. Modeling and measurements of beam and storage ring properties, from proton targeting to muon storage, produce a unique unification of particle beam physics with a high energy physics experiment. Here the beam dynamics issues and analysis techniques essential to the g-2 experiment are presented and discussed.

43 PARTICLE ACCELERATORS↗

DOE OSTI2022

Ferrite-Free Circulator for Precise Measurements of SRF Cavities with High Q-Factor

In this work, we suggest and investigate new magnetless circulators based on three resonators connected in a loop and parametrically modulated in time with mutual phase lag. The first design consists of three Fano resonators with a spectrally asymmetric response, in contrast to schemes based on the Lorentz resonators explored thus far. The second design includes three Fano-Lorentz resonators, i.e., it also possesses spatial asymmetry. We demonstrate that the asymmetric approach provides strong and reversible isolation for the practically feasible modulation amplitude and rate. The results of our work are promising for precise measurements of superconducting radio frequency cavities with high Q-factor.

43 PARTICLE ACCELERATORS↗

DOE OSTI2022

Multidimensional, high precision beam spin asymmetry measurements of semi-inclusive pion production off the proton with CLAS12

High precision measurements of the polarized electron beam-spin asymmetry in SIDIS from the proton have been performed using a 10.6 GeV incident electron beam and the CLAS12 spectrometer at Jefferson Lab. The proceeding reports a multidimensional study of the structure function ratio F^{sin\phi}_{LU}/F_{UU} F L U s i n ϕ / F U U extracted from single pion ( \pi^{+} π + , \pi^{-} π − , \pi^{0} π 0 ) SIDIS data over a large kinematic range in z z , x_{B} x B , P_{T} P T and virtualities Q^{2} Q 2 ranging from 1~GeV ^2 2 up to 7~GeV ^2 2 . F^{sin\phi}_{LU} F L U s i n ϕ is a twist-3 quantity that can reveal novel properties of quark-gluon correlations within the nucleon.

Diehl, Stefan↗

DOE OSTI2014

Precision Studies of Hadronic and Electro-Weak Interactions for Collider Physics (Final Report)

This project was directed toward developing precision computational tools for proton collisions at the Large Hadron Collider, focusing primarily on electroweak boson production and electroweak radiative corrections. The programs developed under this project carried the name HERWIRI, for High Energy Radiation With Infra-Red Improvements, and are the first steps in an ongoing program to develop a set of hadronic event generators based on combined QCD and QED exponentiation. HERWIRI1 applied these improvements to the hadronic shower, while HERWIRI2 will apply the electroweak corrections from the program KKMC developed for electron-positron scattering to a hadronic event generator, including exponentiated initial and final state radiation together with first-order electroweak corrections to the hard process. Some progress was also made on developing differential reduction techniques for hypergeometric functions, for application to the computation of Feynman diagrams.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

DOE OSTI2014

A precision measurement of the neutron 2 . Probing the color force

The g 2 nucleon spin-dependent structure function measured in electron deep inelastic scattering contains information beyond the simple parton model description of the nucleon. It provides insight into quark-gluon correlations and a path to access the confining local color force a struck quark experiences just as it is hit by the virtual photon due to the remnant di-quark. The quantity d 2 , a measure of this local color force, has its information encoded in an x 2 weighted integral of a linear combination of spin structure functions g 1 and g 2 and thus is dominated by the valence-quark region at large momentum fraction x. To date, theoretical calculations and experimental measurements of the neutron d 2 differ by about two standard deviations. Therefore, JLab experiment E06-014, performed in Hall A, made a precision measurement of this quantity at two mean four momentum transfers values of 3.21 and 4.32 GeV 2 . Double spin asymmetries and absolute cross-sections were measured in both DIS and resonance regions by scattering longitudinally polarized electrons at beam energies of 4.74 and 5.89 GeV from a longitudinally and transversely polarized 3 He target. Results for the absolute cross-sections and spin structure functions on 3 He will be presented in the dissertation, as well as results for the neutron d 2 and extracted color forces.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗