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DOE OSTI2022

Superoxide Dismutase 1 Folding Stability as a Target for Molecular Tweezers in SOD1-Related Amyotrophic Lateral Sclerosis

Protein misfolding and aggregation are hallmarks of many severe neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's disease. As a supramolecular ligand that binds to lysine and arginine residues, the molecular tweezer CLR01 was found to modify the aggregation pathway of disease-relevant proteins in vitro and in vivo with beneficial effects on toxicity. However, the molecular mechanisms of how tweezers exert these effects remain mainly unknown, hampering further drug development. Here, we investigate the modulation mechanism of unfolding and aggregation pathways of SOD1, which are involved in amyotrophic lateral sclerosis (ALS), by CLR01. Using a truncated version of the wildtype SOD1 protein, SOD1 bar , we show that CLR01 acts on the first step of the aggregation pathway, the unfolding of the SOD1 monomer. CLR01 increases, by ~10 °C, the melting temperatures of the A4V and G41D SOD1 mutants, which are commonly observed mutations in familial ALS. Molecular dynamics simulations and binding free energy calculations as well as native mass spectrometry and mutational studies allowed us to identify K61 and K92 as binding sites for the tweezers to mediate the stability increase. The data suggest that the modulation of SOD1 conformational stability is a promising target for future developments of supramolecular ligands against neurodegenerative diseases.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2025

Measurement of the top-quark pole mass in dileptonic $t\overline{t}$ + 1-jet events at $\sqrt{s}=13$ TeV with the ATLAS experiment

A measurement of the top-quark pole mass $m$$^{pole}_{t}$ is presented in $t\bar{t}$ events with an additional jet, $t\bar{t}$+ 1-jet, produced in pp collisions at $\sqrt{s} = 13 TeV. The data sample, recorded with the ATLAS experiment during Run 2 of the LHC, corresponds to an integrated luminosity of 140 fb −1 . Events with one electron and one muon of opposite electric charge in the final state are selected to measure the $t\bar{t}$ + 1-jet differential cross-section as a function of the inverse of the invariant mass of the $t\bar{t}$ + 1-jet system. Iterative Bayesian Unfolding is used to correct the data to enable comparison with fixed-order calculations at next-to-leading-order accuracy in the strong coupling. The process pp → $t\bar{t}$j(2 → 3), where top quarks are taken as stable particles, and the process pp → $b\bar{b}$l + vl – $\overline{ν}$j (2 → 7), which includes top-quark decays to the dilepton final state and off-shell effects, are considered. The top-quark mass is extracted using a χ 2 fit of the unfolded normalized differential cross-section distribution. The results obtained with the 2 → 3 and 2 → 7 calculations are compatible within theoretical uncertainties, providing an important consistency check.

Hadron-Hadron Scattering↗

DOE OSTI2025

Measurement of three-dimensional inclusive muon-neutrino charged-current cross sections on argon with the MicroBooNE detector

We report the measurement of the triple-differential cross section d 3 σ/dE vis d cos(θ μ )dP μ for inclusive muon-neutrino charged-current scattering on argon. This measurement utilizes data from 6.4 x 10 20 protons on target of exposure collected using the MicroBooNE liquid argon time projection chamber located along the Fermilab Booster Neutrino Beam with a mean neutrino energy of approximately 0.8 GeV. The mapping from reconstructed kinematics to truth quantities is validated within uncertainties by comparing the distribution of reconstructed hadronic energy in data to that of the model prediction in different muon scattering angle bins after applying a conditional constraint from the muon momentum distribution in data. The success of this validation provides confidence that the energy transfer in the MicroBooNE detector is well-modeled within simulation uncertainties, enabling a reliable unfolding to a triple-differential cross section defined at the nominal neutrino flux over muon momentum, muon scattering angle, and visible neutrino energy. This validation not only supports accurate cross-section extraction, but also establishes a critical foundation for tuning interaction models used in future neutrino oscillation measurements. The unfolded measurement covers an extensive phase space, providing a wealth of information useful for future liquid argon time projection chamber experiments measuring neutrino oscillations. Comparisons against a number of commonly used model predictions are included and their performance in different parts of the available phase-space is discussed.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

DOE OSTI2025

Generation of a fluorescent short-lifetime oxygen nanosensor by coupling of an exciplex forming dye pair

Typical oxygen-sensitive dyes have lifetimes in the μs-ms regime for sensitive oxygen detection based on molecular quenching. Due to the long triplet-state lifetimes and poor quenching efficiency of these probes, it has been difficult to develop short lifetime probes. We have developed oxygen sensors using a short-lifetime dye (∼30–60 ns) that forms an anthracene-aniline exciplex, which is quenched by molecular oxygen through an excited-state charge transfer mechanism. To achieve measurements in aqueous systems, we have tethered the dyes together via a C3 alkyl linker to facilitate greater exciplex formation at low dye concentration (20 μg mL −1 ) and encapsulated the resulting compound into polymeric nanoparticles to form an aqueous-dispersible short-lifetime oxygen nanosensor. The sensors emit at 420 nm (unfolded dye) and 500 nm (exciplex), and the ratiometric Stern-Volmer Constant is 1.52 ± 0.02 L mol −1 , showing good sensitivity from 0 % to 40 % dissolved oxygen without the tradeoff of a long lifetime needed for direct molecular quenching. In this paper, we characterize this sensor for both lifetime-based measurements using time-correlated single-photon counting and ratiometric intensity-based measurements using the unfolded dye emission as an internal reference peak.

Biological and medical sciences↗

DOE OSTI2026

A tunable autonomous RNA-fueled micro-engine

Autonomous molecular machines capable of converting chemical energy into mechanical motion are foundational components for synthetic nanoscale systems. Inspired by biological motors, we report the construction of a tunable, RNA-fueled DNA origami engine that drives the cyclic movement of a 500 nm-diameter particle at the microscale. The engine operates via sequential RNA–DNA hybridization and enzymatic cleavage by RNase H, enabling reversible switching between folded and unfolded conformations without external intervention. By modulating RNA and enzyme concentrations and controlling temperature, we achieve tunable switching kinetics, with transition periods as short as ~10 s. Kinetic modeling reveals that the folding pathway is governed by both productive RNA binding and the enzymatic clearance of misfolded intermediates, while unfolding is primarily controlled by RNase H activity. Since the RNA fuel binds specifically to the DNA strands, each engine is addressable simply by changing the sequences. This work demonstrates a programmable, self-resetting molecular actuator and offers a blueprint for building more complex nanomechanical systems with forces and energies comparable to molecular motors.

DNA nanomachines↗

DOE OSTI2024

Dynamics of ER stress-induced gene regulation in plants

Endoplasmic reticulum (ER) stress is a potentially lethal condition that is induced by the abnormal accumulation of unfolded or misfolded secretory proteins in the ER. In eukaryotes, ER stress is managed by the unfolded protein response (UPR) through a tightly regulated, yet highly dynamic, reprogramming of gene transcription. Although the core principles of the UPR are similar across eukaryotes, unique features of the plant UPR reflect the adaptability of plants to their ever-changing environments and the need to balance the demands of growth and development with the response to environmental stressors. Here, the past decades have seen notable progress in understanding the mechanisms underlying ER stress sensing and signaling transduction pathways, implicating the UPR in the effects of physiological and induced ER stress on plant growth and crop yield. Facilitated by sequencing technologies and advances in genetic and genomic resources, recent efforts have driven the discovery of transcriptional regulators and elucidated the mechanisms that mediate the dynamic and precise gene regulation in response to ER stress at the systems level.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Spectral characterization of flash and high flux x-ray radiographic sources with a magnetic Compton spectrometer

In this article, we present a new analysis method applied to revitalize permanent magnet Compton spectrometers used to measure photon energy spectra in the MeV range. The inversion of the measured electron distribution to determine the original photon distribution is achieved via a method of consistent coupled radiation transport and magnetic field mapping of the input photon spectra to the measured electron distribution. The method of linear least squares was used to perform the unfolding of the electron distribution to the initial photon spectra, without any assumptions made regarding the electron distribution. We present an application of this method to data from a nominal 19.4 MeV flash radiographic source (the first axis of the Dual Axis Radiographic Hydro-Test Facility) capable of generating 500 R @ 1 m in ~60 ns and a medical therapy source (a Scanditronix M22, Microtron) capable of variable energies with nominal endpoints of 6, 10, 15, and 20 MeV and an output of ~1000–2000 R/min @ 1 m. The results provide agreement between the modeled and unfolded experimentally measured photon spectra as quantified by statistical tests, from 1.5 to 20 MeV. Experimental results are presented as well as a discussion of the novel MCNP6-based simulations and methods for reconstruction of the spectra.

47 OTHER INSTRUMENTATION↗

DOE OSTI2024

Inclusive cross section measurements in final states with and without protons for charged-current ν μ -Ar scattering in MicroBooNE

A detailed understanding of inclusive muon neutrino charged-current interactions on argon is crucial to the study of neutrino oscillations in current and future experiments using liquid argon time projection chambers. To that end, we report a comprehensive set of differential cross section measurements for this channel that simultaneously probe the leptonic and hadronic systems by dividing the channel into final states with and without protons. Measurements of the proton kinematics and proton multiplicity of the final state are also presented. For these measurements, we utilize data collected with the MicroBooNE detector from 6.4 × 10 20 protons on target from the Fermilab booster neutrino beam at a mean neutrino energy of approximately 0.8 GeV. We present in detail the cross section extraction procedure, including the unfolding, and model validation that uses data to model comparisons and the conditional constraint formalism to detect mismodeling that may introduce biases to extracted cross sections that are larger than their uncertainties. The validation exposes insufficiencies in the overall model, motivating the inclusion of an additional data-driven reweighting systematic to ensure the accuracy of the unfolding. The extracted results are compared to a number of event generators and their performance is discussed with a focus on the regions of phase space that indicate the greatest need for modeling improvements. Published by the American Physical Society 2024

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

DOE OSTI2022

Joint Determination of Reactor Antineutrino Spectra from U 235 and Pu 239 Fission by Daya Bay and PROSPECT

A joint determination of the reactor antineutrino spectra resulting from the fission of 235U and 239Pu has been carried out by the Daya Bay and PROSPECT collaborations. This Letter reports the level of consistency of 235U spectrum measurements from the two experiments and presents new results from a joint analysis of both data sets. The measurements are found to be consistent. The combined analysis reduces the degeneracy between the dominant 235U and 239Pu isotopes and improves the uncertainty of the 235U spectral shape to about 3%. The 235U and 239Pu antineutrino energy spectra are unfolded from the jointly deconvolved reactor spectra using the Wiener-SVD unfolding method, providing a data-based reference for other reactor antineutrino experiments and other applications. This is the first measurement of the 235U and 239Pu spectra based on the combination of experiments at low- and highly enriched uranium reactors.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

DOE OSTI2025

Search for an Anomalous Production of Charged-Current 𝜈 𝑒 Interactions without Visible Pions across Multiple Kinematic Observables in MicroBooNE

This Letter presents an investigation of low-energy electron-neutrino interactions in the Fermilab Booster Neutrino Beam by the MicroBooNE experiment, motivated by the excess of electron-neutrino-like events observed by the MiniBooNE experiment. This is the first measurement to use data from all five years of operation of the MicroBooNE experiment, corresponding to an exposure of 1.11 × 10 21 protons on target, a 70% increase on past results. Two samples of electron neutrino interactions without visible pions are used, one with visible protons and one without any visible protons. The MicroBooNE data show reasonable agreement with the nominal prediction, with 𝑝 values ≥26.7% when the two 𝜈 𝑒 samples are combined, though the prediction exceeds the data in limited regions of phase space. The data are further compared to two empirical models that modify the predicted rate of electron-neutrino interactions in different variables in the simulation to match the unfolded MiniBooNE low energy excess. In the first model, this unfolding is performed as a function of electron neutrino energy, while the second model aims to match the observed shower energy and angle distributions of the MiniBooNE excess. This measurement excludes an electronlike interpretation of the MiniBooNE excess based on these models at >99% CLs in all kinematic variables.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

DOE OSTI2021

Unraveling Cu Chemical Signature in CdTe by Spectral Fluorescence Mapping

X-ray absorption spectroscopy (XAS) has been shown to be a powerful tool to unravel the chemical environment of a given atom within a matrix. When used in correlative X-ray microscopy approaches, XAS allows one to probe with nanoscale precision regions of particular interest in an absorber. Herein, we use X-ray absorption near edge structure (XANES) to evaluate the chemical environment of Cu atoms within a CdTe solar cell. The reconstruction of XANES spectra from XRF maps have unfolded 2D maps of Cu chemical structures. In this work, we found that most Cu atoms exist in Cu 2 Te and Cu 1.4 Te phase. Moreover, we found traces of CuTe, Cu 2 O, CuO, Cu 2 S, CuS, and metallic Cu phase. Investigating Cu chemical structures at different performing areas, we found no observable correlation between Cu chemical structures and electrical performance. This approach allows tracking of Cu chemical structures along with electrical performance and elemental distribution simultaneously, with high spatial resolution in a statistically practical way.

CdTe↗

DOE OSTI2025

Computational design of potent and selective binders of BAK and BAX

Potent and selective binders of the key proapoptotic proteins BAK and BAX have not been described. We use computational protein design to generate high affinity binders of BAK and BAX with greater than 100-fold specificity for their target. Both binders activate their targets when at low concentration, driving pore formation, but inhibit membrane permeabilization when in excess. Crystallography shows that the BAK binder induces BAK unfolding, exposing the α6 helix and BH3 domain. Together, these data suggest that upon binding, BAK or BAX unfold; at high binder concentrations, self-association of the partially folded BAK or BAX proteins is blocked and the membrane remains intact, whereas at low concentrations, dimers form, and the membrane ruptures. Our designed binders modulate apoptosis via direct, specific interactions with BAK and BAX and reveal that for therapeutic strategies targeting BAK and BAX, inhibition requires saturating binder concentrations at the site of action.

Berger, Stephanie↗

DOE OSTI2025

Structural analysis of extracellular ATP-independent chaperones of streptococcal species and protein substrate interactions

ABSTRACT During infection, bacterial pathogens rely on secreted virulence factors to manipulate the host cell. However, in gram-positive bacteria, the molecular mechanisms underlying the folding and activity of these virulence factors after membrane translocation are not clear. Here, we solved the protein structures of two secreted parvulin and two secreted cyclophilin-like peptidyl-prolyl isomerase (PPIase) ATP-independent chaperones found in gram-positive streptococcal species. The extracellular parvulin-type PPIase, PrsA inStreptococcus pneumoniaeandStreptococcus mutansmaintain dimeric crystal structures reminiscent of folding catalysts that consist of two domains, a PPIase and foldase domain. Structural comparison of the two cyclophilin-like extracellular chaperones fromS. pneumoniaeandStreptococcus pyogeneswith other cyclophilins demonstrates that this group of cyclophilin-like chaperones has novel structural appendages formed by 9- and 24-residue insertions. Furthermore, we demonstrate that deletion ofprsAandslrAgenes impairs the secretion of the cholesterol-dependent pore-forming toxin, pneumolysin inS. pneumoniae. Using protein pull-down and biophysical assays, we demonstrate a direct interaction between PrsA and SlrA with Ply. Then, we developed chaperone-assisted folding assays that show that theS. pneumoniaePrsA and SlrA extracellular chaperones accelerate pneumolysin folding. In addition, we demonstrate that SlrA and, for the first time,S. pyogenes PpiA exhibit PPIase activity and can bind the immunosuppressive drug, cyclosporine A. Altogether, these findings suggest a mechanistic role for streptococcal PPIase chaperones in the activity and folding of secreted virulence factors such as pneumolysin. IMPORTANCE Streptococcal species are a leading cause of lower respiratory infections that annually affect millions of people worldwide. During infection, streptococcal species secrete a medley of virulence factors that allow the bacteria to colonize and translocate to deeper tissues. In many gram-positive bacteria, virulence factors are secreted from the cytosol across the bacterial membrane in an unfolded state. The bacterial membrane-cell wall interface is exposed to the potentially harsh extracellular environment, making it difficult for native virulence factors to fold before being released into the host. ATP-independent PPIase-type chaperones, PrsA and SlrA, are thought to facilitate folding and stabilization of several unfolded proteins to promote the colonization and spread of streptococci. Here, we present crystal structures of the molecular chaperones of PrsA and SlrA homologs from streptococcal species. We provide evidence that theStreptococcus pyogenesSlrA homolog, PpiA, has PPIase activity and binds to cyclosporine A. In addition, we show thatStreptococcus pneumoniaePrsA and SlrA directly interact and fold the cholesterol-dependent pore-forming toxin and critical virulence determinant, pneumolysin.

Microbiology↗

DOE OSTI2025

Seasonal variations of the atmospheric muon neutrino spectrum measured with IceCube

This study presents an analysis of seasonal variations in the atmospheric muon neutrino flux, using 11.3 years of data from the IceCube Neutrino Observatory. By leveraging a novel spectral unfolding method, we explore the energy range from 125 GeV to 10 TeV for zenith angles from 90° to 110°, corresponding to the Antarctic atmosphere. Our findings reveal that the differential measurement of the amplitudes of the seasonal variation is consistent with an energy-dependent decrease reaching (-4.5 ± 1.2)% during Austral winter and increase to (+ 3.9 ± 1.3)% during Austral summer relative to the annual average at 10 TeV. While the unfolded flux exceeds the model predictions by up to 30%, the differential measurement of the seasonal to annual average flux remains unaffected. The measured seasonal variations of the muon neutrino spectrum are consistent with theoretical predictions using the MCEq code and the NRLMSISE-00 atmospheric model.

Astroparticle Physics and High-Energy Cosmic Pheno↗

DOE OSTI2024

Inhibition of the eukaryotic initiation factor-2α kinase PERK decreases risk of autoimmune diabetes in mice

Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress–responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eukaryotic translation initiation factor-2α (eIF2α). In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity. We found that inhibition of the eIF2α kinase PKR-like ER kinase (PERK), a common component of the UPR and ISR, reversed the mRNA translation block in stressed human islets and delayed the onset of diabetes, reduced islet inflammation, and preserved β cell mass in T1D-susceptible mice. Single-cell RNA-Seq of islets from PERK-inhibited mice showed reductions in the UPR and PERK signaling pathways and alterations in antigen-processing and presentation pathways in β cells. Spatial proteomics of islets from these mice showed an increase in the immune checkpoint protein programmed death-ligand 1 (PD-L1) in β cells. Golgi membrane protein 1, whose levels increased following PERK inhibition in human islets and EndoC-βH1 human β cells, interacted with and stabilized PD-L1. Collectively, our studies show that PERK activity enhances β cell immunogenicity and that inhibition of PERK may offer a strategy for preventing or delaying the development of T1D.

Research & Experimental Medicine↗

DOE OSTI2024

Returning CP-observables to the frames they belong

Optimal kinematic observables are often defined in specific frames and then approximated at the reconstruction level. We show how multi-dimensional unfolding methods allow us to reconstruct these observables in their proper rest frame and in a probabilistically faithful way. We illustrate our approach with a measurement of a CP-phase in the top Yukawa coupling. Our method makes use of key advantages of generative unfolding, but as a constructed observable it fits into standard LHC analysis frameworks.

Physics↗

DOE OSTI2021

Universal Monte Carlo Event Generator

With the Jefferson Lab 12 GeV physics program underway and plans for the future Electron-Ion Collider (EIC), the nuclear physics community is entering a new era of exploration of QCD phenomena involving extensive data taking and event-level processing. This brings with it the potential for unprecedented access to multidimensional particle momentum distributions (PMDs) that can be connected to various theoretical frameworks by unfolding the emergent quantum mechanical properties of QCD using the PMDs. In practice, the PMDs are rendered as discretized histograms (typically one- or two-dimensional projections), and detector effects must be taken into account to unfold the pure detector effect-free PMDs that can be connected with theory. One of the challenges in this new era is obtaining faithful reconstructions of the multidimensional PMDs that preserve all of the inherent particle correlations. In this LDRD project we developed a novel approach using machine learning (ML) that solves this challenge, by avoiding entirely the need to use histograms as the main numerical technique to obtain the detector effect-free PMDs. The new approach is, moreover, scalable to higher dimensional PMDs. The central idea involves training neural networks (NNs) to generate synthetic event-level data (momenta 4-vectors of final state particles) to preserve all correlations among the particles. This is achieved by converting the trial synthetic vertex-level events to detector-level events using detector simulators. The NNs are then tuned using a specialized distance metric between the synthetic detector events and the real detector events.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

DOE OSTI2021

Measuring Saturn's Electron Beam Energy Spectrum using Webb's Wedges

It is very difficult to measure the voltage of the load on the Saturn accelerator. Time-resolved measurements such as vacuum voltmeters and V-dot monitors are impractical at best and completely change the pulsed power behavior at the load at worst. We would like to know the load voltage of the machine so that we could correctly model the radiation transport and tune our x-ray unfold methodology and circuit simulations of the accelerator. Step wedges have been used for decades as a tool to measure the end - point energies of high energy particle beams. Typically, the technique is used for multi-megavolt accelerators, but we have adapted it to Saturn's modest <2 MV end-point energy and modified the standard bremsstrahlung x-ray source to extract the electron beam without changing the physics of the load region. We found clear evidence of high energy electrons >2 MV. We also attempted to unfold an electron energy spectrum using a machine learning algorithm and while these results come with large uncertainties, they qualitatively agree with PIC simulation results.

43 PARTICLE ACCELERATORS↗