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At least 217 records · Page 12

Production, isolation, and shipment of clinically relevant quantities of astatine-211: A simple and efficient approach to increasing supply

The alpha emitter astatine-211 ( 211 At) is a promising candidate for cancer treatment based on Targeted Alpha (α) Therapy (TAT). A small number of facilities, distributed across the United States, are capable of accelerating α-particle beams to produce 211 At. However, challenges remain regarding strategic methods for shipping 211 At in a form adaptable to advanced radiochemistry reactions and other uses of the radioisotope. Purpose: Our method allows shipment of 211 At in various quantities in a form convenient for further radiochemistry. Procedures: For this study, a 3-octanone impregnated Amberchrom® CG300M resin bed in a column cartridge was used to separate 211 At from the bismuth matrix on site at the production accelerator (Texas A&M) in preparation for shipping. Aliquots of 6 M HNO 3 containing up to ≈2.22 GBq of 211 At from the dissolved target were successfully loaded and retained on columns. Exempt packages (<370 MBq) were shipped to a destination radiochemistry facility, University of Texas MD Anderson Cancer Center, in the form of a convenient air-dried column. Type A packages have been shipped overnight to University of Alabama at Birmingham. Main findings: Air-dried column hold times of various lengths did not inhibit simple and efficient recovery of 211 At. Solution eluted from the column was sufficiently high in specific activity to successfully radiolabel a model compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1), with 211 At. The method to prepare and ship 211 At described in this manuscript has also been used to ship larger quantities of 211 At a greater distance to University of Alabama at Birmingham. Principal conclusions: The successful proof of this method paves the way for the distribution of 211 At from Texas A&M University to research institutions and clinical oncology centers in Texas and elsewhere. Finally, use of this simple method at other facilities has the potential increase the overall availability of 211 At for preclinical and clinical studies.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Evaluation of the beam-induced depolarization of the HJET target at the EIC

The Polarized Atomic Hydrogen Gas Jet Target (HJET) has played a central role in the absolute calibration of proton beam polarization at RHIC and is foreseen as a key component of the hadron polarimetry program at the future Electron–Ion Collider (EIC). The substantially higher beam current, reduced bunch spacing, and shorter bunch length planned for EIC operation motivate a careful reassessment of possible beam-induced depolarization of the jet target. In this paper, the depolarization of ground-state hydrogen atoms caused by the time-dependent magnetic field of the circulating polarized proton beam is quantitatively evaluated. The hydrogen atom is treated as a four-level hyperfine system in a holding magnetic field, and transitions driven by harmonic components of the bunch-induced magnetic field are analyzed using time-dependent quantum-mechanical evolution along atomic trajectories. Numerical tracking of hydrogen atoms through the beam region is performed using nominal EIC beam parameters. It is shown that, for a holding field of 120 mT (as used at RHIC), the resulting depolarization of the jet target at the EIC is negligibly small, ≲ 0.01 %, and well below the level relevant for EIC polarization accuracy requirements. The stability of this result with respect to plausible variations of the EIC proton beam parameters is also evaluated. In addition, possible effects under alternative experimental conditions are also examined.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

The research challenges in security and safeguards for nuclear fission batteries

This paper discusses the nuclear security and safeguards research challenges presented by the development and deployment of nuclear fission batteries. These are defined as easily transportable and deployable nuclear systems which are designed to operate either unattended or autonomously. We start by defining the current landscape of domestic and international safeguards and security and discuss how it can be affected by the introduction these new nuclear systems. We then specifically discuss the technology gaps and technologies to be developed to facilitate their practical deployment. We find that, as expected, we can leverage conclusions from existing security and safeguards studies for small modular rectors and develop bespoke target set analyses to inform security postures based on probabilistic risk assessment. We find also that specific fission battery security economic analysis tools are needed and security by design must be applied early. However, the most important finding is that these new systems will require a new comprehensive set of cyber tools covering transportation, installation, operation, maintenance security of the fission battery systems. Altogether, we find that the development of the necessary security and safeguards requirements at the design phase of such a technology will be of great benefit in the smooth deployment of this modern nuclear energy system.

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗

Melt-Spun PAN Precursor for Cost-Effective Carbon Fibers in High Pressure Compressed Gas Tankage

The objective of this program was to synthesize melt-spinnable polyacrylonitrile (PAN) precursor that will lead to carbon fiber 25% less expensive than carbon fiber produced from conventional PAN precursor when produced in large volumes. The carbon fiber produced from this precursor needs to achieve ≥ 700 ksi tensile strength with this cost reduction to replace the incumbent fiber. In this program, the technology for producing precursor and then converted carbon fiber (CF) capable of meeting the 700 ksi target was to be demonstrated at a small scale in tows, containing ≥ 100 filaments. If this program moved on to a “Phase 2”, the processes would be scaled up to produce and test Type IV compressed gas storage tanks capable of meeting the 700-bar ultimate targeted FOA performance level. Precursor fiber production typically contributes a large fraction (~50%) to finished CF manufactured cost. Presently, all high strength CFs are manufactured from solution spun PAN precursor, accomplished at low temperatures using large amounts of environmentally unfriendly solvents that impart major impact to line speed and costs involved with handling and reclaiming the solvents and associated “waste streams” required in spinning and extracting those solvents. PAN melt spinning was demonstrated by the company BASF in CF precursor production and used in production of some other acrylic fibers, but significant production challenges remain for meeting the established CF metrics. Melt spinning requires use of plasticizers to suppress the melt temperature of the predominantly PAN formulation to a point sufficiently below the temperature of significant cross-linking. Fortunately, BASF and this team’s earlier work had demonstrated acrylic formulations melt spun with combinations of plasticizing solvents at much lower solvent levels. This project team made significant progress in understanding technical issues and identifying formulation pathways in earlier work in this area where >250ksi strength was achieved. The goal of this program was to pursue a more comprehensive approach with a larger, more diverse team having greater equipment design and overall production capabilities to push rapidly beyond the science to resolve remaining “engineering” issues associated with establishing stable, continuous processes for precursor fiber leading to enhanced, cost-effective CF and composite tank production.

36 MATERIALS SCIENCE↗

Gluon-mediated inclusive Deep Inelastic Scattering from Regge to Bjorken kinematics

We revisit high energy factorization for gluon mediated inclusive Deep Inelastic Scattering (DIS) for which we propose a new semi-classical approach that accounts systematically for the longitudinal extent of the target in contrast with the shockwave limit. In this framework, based on a partial twist expansion, we derive a factorization formula that involves a new gauge invariant unintegrated gluon distribution which depends explicitly on the Feynman x variable. It is shown that both the Regge and Bjorken limits are recovered in this approach. We reproduce in particular the full one loop inclusive DIS cross-section in the leading twist approximation and the all-twist dipole factorization formula in the strict x = 0 limit. Although quantum evolution is not discussed explicitly in this work, we argue that the proper treatment of the x dependence of the gluon distribution encompasses the kinematic constraint that must be imposed on the phase-space of gluon fluctuations in the target to ensure stability of small-x evolution.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗

Multicomponent gas mixture parametric CFD study of condensation heat transfer in small modular reactor system safety

Safety is always the primary concern for designing and analyzing nuclear reactor systems. The requirements for the safety margin for advanced small modular reactor (SMR) systems are targeted even higher than the conventional commercial large-scale nuclear reactors incorporating the passive and inherent safety systems. The SMR systems are designed with the condensation passive containment cooling system (PCCS), which plays a critical role in removing reactor heat during a steam release accident case. However, the presence of non-condensable gas (NCG), like air, reduces the heat transfer performance. This physics phenomenon becomes multifactorial for nuclear reactor containment during a fuel failure accident case that releases hydrogen gas. Besides, the mixture component of steam-air-hydrogen varies in reactor accident cases, which need simulation and validation keeping parameters of importance. Reviews showed that previous studies for SMR’s PCCCS did not cover the condensation heat transfer (CHT) in the presence of multicomponent NCG mixture parametric computational fluid dynamics (CFD) simulation and validation, making a research gap in the SMR design safety. A comprehensive CHT parametric CFD study was performed for SMR PCCS to fill this research gap. This study used experimental data as simulation 3D physics domain inlet and outlet boundary conditions. However, the wall boundary conditions were constant temperature, curve-fit, and annular coolant for verifying the turbulence models. Parametric simulations were performed, verified, and optimized for steam-NCGs mixtures. The multicomponent gases, multiphase mixtures, and fluid film condensation models were applied with associated turbulence models. The results of the parametric study were evaluated for realistic reactor conditions. Results showed that parametric study provided critical insight about the dependency of multicomponent gas mixture parameters that supports reactor safety design, analysis, and licensing.

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗

Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET

A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non–small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain—Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.

59 BASIC BIOLOGICAL SCIENCES↗

Dynamic PRA Methods to Evaluate the Impact on Accident Progression of Accident Tolerant Fuels

Accident tolerant fuels (ATFs) are new nuclear fuels developed in response to the accident at the Fukushima power station in March 2011. The goal of ATFs is to withstand accident scenarios through better performance compared to currently employed fuels (e.g., small-scale hydrogen generation). This paper targets a method for evaluating and comparing ATF performance from a probabilistic risk assessment (PRA) perspective by employing a newly developed combination of event trees and dynamic PRA methods. Compared to classical PRA methods based on event trees and fault trees, dynamic PRA can evaluate with higher resolution the safety impacts of physics dynamics and the timing/sequencing of events on the accident progression without the need to introduce overly conservative modeling assumptions and success criteria. In this paper, we analyze the impact on the accident progression of three different cladding configurations for two initiating events [a large break loss-of-coolant accident (LB-LOCA) and a station blackout (SBO)] by employing dynamic PRA methods. The goal is to compare the safety performance of ATFs (FeCrAl and Cr-coated cladding) and the currently employed Zr-based clad fuel. We employ two different strategies. The first focuses on the identification of success criteria discrepancies between the accident sequences generated by the classical PRA model and the set of simulation runs generated by dynamic PRA using ATF. The second one, on the other hand, directly uses dynamic PRA to evaluate the impact of timing of events (e.g., recovery actions) on accident progression. In conclusion, by applying these methods to the LB-LOCA and SBO initiating events, we show how dynamic PRA methods can provide analysts with detailed and quantitative information on the safety impact of ATFs.

97 - MATHEMATICS AND COMPUTING↗

Production and testing of the large-area photon detector ArCLight

Compact large-area dielectric photon detectors that ensure modular noble liquid detectors can sense scintillation light signals for triggering and reconstruction purposes with minimal impact to the overall target volume. ArCLight is a small-volume, sizeable sensitive-area detector that consists of a light trap covered in a thin layer of TPB that can be placed inside a time projection chamber's electric field. These sensors are used in the Deep Underground Neutrino Experiment Near Detector liquid argon (DUNE ND-LAr). They are constructed and tested at the University of Bern and will be deployed in the prototype experiment ProtoDUNE-ND. The talk discusses the details of assembling ArCLights, the quality control methods, and the test studies done with LEDs to assess their performance.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Novobiocin blocks nucleic acid binding to Polθ and inhibits stimulation of its ATPase activity

Polymerase theta (Polθ) acts in DNA replication and repair, and its inhibition is synthetic lethal in BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB) is a first-in-class inhibitor of the Polθ ATPase activity, and it is currently being tested in clinical trials as an anti-cancer drug. Here, we investigated the molecular mechanism of NVB-mediated Polθ inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational and cellular assays, we found NVB is a non-competitive inhibitor of ATP hydrolysis. NVB sugar group deletion resulted in decreased potency and reduced HX-MS interactions, supporting a specific NVB binding orientation. Collective results revealed that NVB binds to an allosteric site to block DNA binding, both in vitro and in cells. Comparisons of The Cancer Genome Atlas (TCGA) tumors and matched controls implied that POLQ upregulation in tumors stems from its role in replication stress responses to increased cell proliferation: this can now be tested in fifteen tumor types by NVB blocking ssDNA-stimulation of ATPase activity, required for Polθ function at replication forks and DNA damage sites. Structural and functional insights provided in this study suggest a path for developing NVB derivatives with improved potency for Polθ inhibition by targeting ssDNA binding with entropically constrained small molecules.

59 BASIC BIOLOGICAL SCIENCES↗

Measurement of the nucleon spin structure functions for 0.01 < 𝑄 2 < 1 GeV 2 using CLAS

The spin structure functions of the proton and the deuteron were measured during the EG4 experiment at Jefferson Lab in 2006. Data were collected for longitudinally polarized electron scattering off longitudinally polarized NH 3 and ND 3 targets, for 𝑄 2 values as small as 0.012 and 0.02 GeV 2 , respectively, using the CEBAF Large Acceptance Spectrometer. This is the archival paper of the EG4 experiment that summarizes the previously reported results of the polarized structure functions 𝑔 1 , 𝐴 1 ⁢𝐹 1 , and their moments $\bar{Γ}$ 1 , $\bar{𝛾}$ 0 , and $\bar{𝐼}$ TT , for both the proton and the deuteron. In addition, we report on new results on the neutron 𝑔 1 extracted by combining proton and deuteron data and correcting for Fermi smearing, and on the neutron moments $\bar{Γ}$ 1 , $\bar{𝛾}$ 0 , and $\bar{𝐼}$ TT formed directly from those of the proton and the deuteron. Our data are in good agreement with the Gerasimov-Drell-Hearn sum rule for the proton, deuteron, and neutron. Furthermore, the isovector combination was formed for 𝑔 1 and the Bjorken integral $\bar{Γ}^{𝑝−𝑛}_1$, and it was compared to available theoretical predictions. All of our results, to the best of our knowledge, provide for the first time extensive tests of spin observable predictions from chiral effective field theory (𝜒⁢EFT) in a 𝑄 2 range commensurate with the pion mass. Finally, they motivate further improvement in 𝜒⁢EFT calculations from other approaches such as the lattice gauge method.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗

Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.

59 BASIC BIOLOGICAL SCIENCES↗

Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA

The human gamma-herpesviruses Epstein–Barr virus (EBV) (HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein–Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KSHV are viral-encoded DNA-binding proteins that are essential for the replication and maintenance of their respective viral genomes during latent, oncogenic infection. As such, EBNA1 and LANA are attractive targets for the development of small-molecule inhibitors. To this end, we performed a biophysical screen of EBNA1 and LANA using a fragment library by saturation transfer difference (STD)–NMR spectroscopy and surface plasmon resonance (SPR). We identified and validated a number of unique fragment hits that bind to EBNA1 or LANA. We also determined the high-resolution crystal structure of one fragment bound to EBNA1. Results from this screening cascade provide new chemical starting points for the further development of potent inhibitors for this class of viral proteins.

59 BASIC BIOLOGICAL SCIENCES↗

Legacy Analysis of Milky Way Dwarf Spheroidal Satellite Galaxies: An Update

Studies of Fermi Large Area Telescope (LAT) data coincident with dwarf spheroidal satellite galaxies (dSphs) of the Milky Way have put the most stringent constraints on models of annihilating dark matter (DM) with candidate masses in the GeV–TeV range. Recent results found the presence of small, local significance excesses from these targets, at the 2σ–3σ level. However, these excesses disagree on the predicted properties of the DM candidate, and their significance vanishes when considering correction factors for the number of trials. In this work, we apply key improvements to the analysis of dSphs. We use stricter cuts on the data, implement a method to adaptively model the background, and assume an updated framework for DM annihilation. We find that our improved background modeling leads to a better agreement between the model and the data. This produces an increase in the local and global significance of the dSph excess compared to previous studies. Finally, we find that the DM properties obtained in this work are less dependent on the sample of dSphs being considered compared to previous studies, while remaining in agreement with the predictions from the Galactic center excess observed by Fermi/LAT and the antiproton excess observed by the Alpha Magnetic Spectrometer (AMS-02). Considering our improvements, a future significant increase in the number of dwarfs may lead to a definitive confirmation or exclusion of the DM interpretation of the Galactic center excess.

cold dark matter↗

Deep learning inversion of gravity data for detection of CO 2 plumes in overlying aquifers

In this work, we developed an effective U-Net based deep learning (DL) model for inversion of surface gravity data on a rectangular grid to predict 2-D high-resolution subsurface CO 2 distribution along a vertical cross-section due to CO 2 leakage through a wellbore within a deep CO 2 storage reservoir. We used synthetic data to model two types of CO 2 leakage scenarios: one CO 2 plume in a shallow aquifer (single plume case), and two plumes present at different depths (double plume case). The 3-D synthetic plume samples were created by sampling among predetermined CO 2 plume depths, saturations, and volumes. The corresponding surface gravity data on a rectangular grid were generated by a 3-D forward model. The U-Net model detected 72% of single-plume samples, and one or both plumes in 75% of double-plume samples. Most of the undetected single plumes have small gravity field strengths below the typical noise level of 5 μGal. This model generated reproducible, reliable predictions with acceptable errors and demonstrated improved spatial resolution over the conventional least-squares inversion. In contrast to the conventional least-squares inversion, which often overestimates the size of its target and underestimates its density, this U-Net model accurately delineated the boundary of a target. Furthermore, this DL inversion detected deep, small, or low saturation CO 2 plumes that are often more difficult to resolve with conventional gravity inversion methods. We note the limitations of this feasibility study, including the use of synthetic data with regular CO 2 plume shapes, and the prediction of a 2-D plume cross-section rather than the full 3-D plume, as well, we recognize the lower detection fraction for double-plume scenarios. Nevertheless, this study demonstrates that DL gravity inversion is a promising and potentially superior method to conventional least-squares inversion. Our U-Net based deep learning inversion approach may be adapted for inversion of other types of geophysical data. DL inversion can facilitate near real-time monitoring of geologic carbon sequestration to provide site operators with prompt information about subsurface CO 2 distribution for risk management and mitigation.

58 GEOSCIENCES↗

Precise Measurement of the Neutron Skin Thicknesses of 208Pb and 48Ca

Despite great leaps of development in nuclear physics over the past century, we still do not have a comprehensive understanding of nuclear structure. This is mainly due to the lack of precise knowledge of the neutron distribution inside nucleus. Electromagnetic probes are ineffective in probing neutrons, unlike their charged partners, the protons. Therefore, it is of great importance to constrain the neutron distributions experimentally. Heavy nuclei have more neutrons than protons in order to balance the repulsion between protons. In such neutron-rich nuclei, the extra neutrons are pushed out to the surface by the nuclear symmetry energy, forming the so-called ?neutron skin?. The neutron skin can be probed with a well-established experimental technique ? parity-violating electron scattering (PVES). Using the scattering of longitudinally polarized electrons by an unpolarized target, PREX-II and CREX measure the small parity-violating asymmetry in cross sections. Employing electrons with opposite helicities the weak form factor, the neutron distribution and the neutron skin thickness of the target nucleus are extracted. With excellent beam qualities and dedicated instrumentation at Jefferson Lab, the asymmetry measurements are statistics-limited. We report the results of these two high-precision measurements and their implications on broad topics, from the nuclear structures to the neutron stars.

Zhang, Weibin↗

Impact of structural biology and the protein data bank on us fda new drug approvals of low molecular weight antineoplastic agents 2019–2023

Abstract Open access to three-dimensional atomic-level biostructure information from the Protein Data Bank (PDB) facilitated discovery/development of 100% of the 34 new low molecular weight, protein-targeted, antineoplastic agents approved by the US FDA 2019–2023. Analyses of PDB holdings, the scientific literature, and related documents for each drug-target combination revealed that the impact of structural biologists and public-domain 3D biostructure data was broad and substantial, ranging from understanding target biology (100% of all drug targets), to identifying a given target as likely druggable (100% of all targets), to structure-guided drug discovery (>80% of all new small-molecule drugs, made up of 50% confirmed and >30% probable cases). In addition to aggregate impact assessments, illustrative case studies are presented for six first-in-class small-molecule anti-cancer drugs, including a selective inhibitor of nuclear export targeting Exportin 1 (selinexor, Xpovio), an ATP-competitive CSF-1R receptor tyrosine kinase inhibitor (pexidartinib,Turalia), a non-ATP-competitive inhibitor of the BCR-Abl fusion protein targeting the myristoyl binding pocket within the kinase catalytic domain of Abl (asciminib, Scemblix), a covalently-acting G12C KRAS inhibitor (sotorasib, Lumakras or Lumykras), an EZH2 methyltransferase inhibitor (tazemostat, Tazverik), and an agent targeting the basic-Helix-Loop-Helix transcription factor HIF-2α (belzutifan, Welireg).

60 APPLIED LIFE SCIENCES↗