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At least 217 records · Page 12

From Intermolecular Interaction Energies and Observable Shifts to Component Contributions and Back Again: A Tale of Variational Energy Decomposition Analysis

Quantum chemistry in the form of density functional theory (DFT) calculations is a powerful numerical experiment for predicting intermolecular interaction energies. However, no chemical insight is gained in this way beyond predictions of observables. Energy decomposition analysis (EDA) can quantitatively bridge this gap by providing values for the chemical drivers of the interactions, such as permanent electrostatics, Pauli repulsion, dispersion, and charge transfer. These energetic contributions are identified by performing DFT calculations with constraints that disable components of the interaction. This review describes the second-generation version of the absolutely localized molecular orbital EDA (ALMO-EDA-II). The effects of different physical contributions on changes in observables such as structure and vibrational frequencies upon complex formation are characterized via the adiabatic EDA. Example applications include red- versus blue-shifting hydrogen bonds; the bonding and frequency shifts of CO, N 2 , and BF bound to a [Ru(II)(NH 3 ) 5 ] 2 + moiety; and the nature of the strongly bound complexes between pyridine and the benzene and naphthalene radical cations. Additionally, the use of ALMO-EDA-II to benchmark and guide the development of advanced force fields for molecular simulation is illustrated with the recent, very promising, MB-UCB potential.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Xavier: High-Performance X-Drop Adaptive Banded Pairwise Alignment (Xavier) v1.0

Pairwise sequence alignment is one of the most compute-intense challenges for the analysis of genomics data and it can account for more than 90% of the runtime depending on the application. Despite the effort to reduce the computational cost introducing heuristics such as banded and x-drop alignment, the performance of state-of-the-art software is often unsatisfactory for long sequences. Recent advances in single-molecule sequencing technologies keep increasing the length of the sequences to align at the cost of higher error rates b ranging from 5% to 15% b, emphasizing the need for fast and accurate software. Our long-read alignment software, named Xavier, computes high-performance x-drop adaptive banded pairwise alignment exploiting instruction-level parallelism via Single-Instruction-Multiple-Data (SIMD) operations. Xavier uses a narrow bandwidth that appreciably improves performance reducing the search space for the optimal alignment. In our experiment, the adaptive mechanism enables Xavier to find the optimal alignment between related sequences even when the error rate is as high as 50%. Xavier achieves speed-up up to 5X over competitor software when enabling the x-drop termination and up to 415X when disabling it, with negligible accuracy loss.

Guidi, Giulia↗

Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C

Abstract Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine, and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor–activated states, in which current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in phase 1 clinical trials in patients with KRASG12C non–small cell lung cancer. Significance: BBO-8520 is a first-in-class direct, small molecule covalent dual inhibitor that engages KRASG12C in the active (ON) and inactive (OFF) conformations. BBO-8520 represents a novel mechanism of action that allows for optimal target coverage and delays the emergence of adaptive resistance seen with (OFF)-only inhibitors in the clinic. See related commentary by Zhou and Westover, p. 455

Oncology↗

Antitumor T-cell Immunity Contributes to Pancreatic Cancer Immune Resistance

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T-cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune resistance in pancreatic cancer was induced in response to antitumor T-cell immune responses and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide evidence that T-cell–dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune resistance. Three KPC mouse models of pancreatic cancer were used: the mT3-2D (Kras +/LSL-G12D ; Trp53 +/LSL-R172H ; Pdx1-Cre) subcutaneous and orthotopic models, as well as the KP1 (p48-CRE/LSL-Kras/Trp53 flox/flox ) subcutaneous model. KPC cancer cells were grown in immunocompetent and immunodeficient C57BL/6 mice and analyzed to determine the impact of adaptive immunity on malignant epithelial cells, as well as on whole tumors. We found that induced T-cell antitumor immunity, via signal transducer and activator of transcription 1 (STAT1), stimulated malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and altered intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA-approved drug ruxolitinib overcame these tumor-protective responses and improved anti–PD-1 therapeutic efficacy. Overall, these findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.

60 APPLIED LIFE SCIENCES↗

Boundary Layer Height and Buoyancy Determine the Horizontal Scale of Convective Self-Aggregation

Organized rainstorms and their associated overturning circulations can self-emerge over an ocean surface with uniform temperature in cloud-resolving simulations. This phenomenon is referred to as convective self-aggregation. Convective self-aggregation is argued to be an important building block for tropical weather systems and may help regulate tropical atmospheric humidity and thereby tropical climate stability. Here the author presents a boundary layer theory for the horizontal scale λ of 2D (x, z) convective self-aggregation by considering both the momentum and energy constraints for steady circulations. This theory suggests that λ scales with the product of the boundary layer height h and the square root of the amplitude of density variation between aggregated moist and dry regions in the boundary layer, and that this density variation mainly arises from the moisture variation due to the virtual effect of water vapor. Furthermore, this theory predicts the following: 1) the order of magnitude of λ is ~2000 km, 2) the aspect ratio of the boundary layer λ/h increases with surface warming, and 3) λ decreases when the virtual effect of water vapor is disabled. These predictions are confirmed using a sui te of cloud-resolving simulations spanning a wide range of climates.

54 ENVIRONMENTAL SCIENCES↗

Cloud Radiative Feedbacks and El Niño–Southern Oscillation

Cloud radiative feedbacks are disabled via “cloud-locking” in the Community Earth System Model, version 1.2 (CESM1.2), to result in a shift in El Niño–Southern Oscillation (ENSO) periodicity from 2–7 years to decadal time scales. We hypothesize that cloud radiative feedbacks may impact the periodicity in three ways: by 1) modulating heat flux locally into the equatorial Pacific subsurface through negative shortwave cloud feedback on sea surface temperature anomalies (SSTA), 2) damping the persistence of subtropical southeast Pacific SSTA such that the South Pacific meridional mode impacts the duration of ENSO events, or 3) controlling the meridional width of off-equatorial westerly winds, which impacts the periodicity of ENSO by initiating longer Rossby waves. The result of cloud-locking in CESM1.2 contrasts that of another study, which found that cloud-locking in a different global climate model led to decreased ENSO magnitude across all time scales due to a lack of positive longwave feedback on the anomalous Walker circulation. CESM1.2 contains this positive longwave feedback on the anomalous Walker circulation, but either its influence on the surface is decoupled from ocean dynamics or the feedback is only active on interannual time scales. The roles of cloud radiative feedbacks in ENSO in other global climate models are additionally considered. In particular, it is shown that one cannot predict the role of cloud radiative feedbacks in ENSO through a multimodel diagnostic analysis. Instead, they must be directly altered.

54 ENVIRONMENTAL SCIENCES↗

Sensitivity of surface temperature to oceanic forcing via q-Flux Green’s function experiments. Part III: asymmetric response to warming and cooling

Climate response is often assumed to be linear in climate sensitivity studies. However, by examining the surface temperature (TS) response to pairs of oceanic forcings of equal amplitude but opposite sign in a large set of local q-flux perturbation experiments with CAM5 coupled to a slab, we find strong asymmetry in TS responses to the heating and cooling forcings, indicating a strong nonlinearity intrinsic to the climate system examined. Regardless of where the symmetric forcing is placed, the cooling response to the negative forcing always exceeds the warming to the positive forcing, implying an intrinsic inclination towards cooling of our current climate. Thus, the ongoing global warming induced by increasing greenhouse gases may have already been alleviated by the asymmetric component of the response. The common asymmetry in TS response peaks in high latitudes, especially along sea ice edges, with notable seasonal dependence. Decomposition into different radiative feedbacks through a radiative kernel indicates that the asymmetry in the TS response is realized largely through lapse rate and albedo feedbacks. Further process interference experiments disabling the seasonal cycle and/or sea ice reveal that the asymmetry originates ultimately from the presence of the sea ice component and is further amplified by the seasonal cycle. The fact that a pair of opposite tropical q-flux forcings can excite very similar asymmetric response as a pair placed at 55°S strongly suggests the asymmetric response is a manifestation of an internal mode of the climate model system.

Liu, Fukai↗

Community Public Mobility Using On-Demand, Low-Speed Electric Vehicles: A Case Study in Downtown St. Louis, Missouri

Legacy fixed route transit systems designed to serve commuters struggle to provide efficient and effective service for short neighborhood trips and for population groups unable to access and egress transit stops using active modes (e.g., elderly, disabled). Neighborhood on-demand transit (ODT) services using low-speed electric vehicles (LSEV) are an innovative technological solution that can help fill this gap in service (e.g., short, high-frequency trips) for diverse populations and trip types. This study evaluated user characteristics and travel behavior for a neighborhood ODT service (using LSEVs) in downtown St. Louis, Missouri using responses from a community survey (n=244), ridership data, and vehicle trajectory information. A comparative analysis between neighborhood ODT, fixed route transit, and transportation network companies (TNC) was also conducted from the perspectives of total travel time, cost, and greenhouse gas emissions. Ultimately, the goal of the analysis was to motivate and inform holistic public mobility systems where different services are optimized to meet specific community needs. Findings indicate that the neighborhood ODT was effective at reaching diverse populations (elderly (20%), lower income (27%), and households with limited access to private vehicles (34%)). ODT reduced total travel time by 32% compared to fixed route transit, produced 2.4 - 4.3 times less greenhouse gas emissions per passenger mile (compared to transit and TNCs), and was more affordable (free to users) than alternative options ($1 for transit, $10-12 for TNCs). Overall satisfaction rates were high, with 80% of respondents rating the service a 4 or 5 out of 5.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗

Progress Toward a Multiomic Understanding of Traumatic Brain Injury: A Review

Traumatic brain injury (TBI) is not a single disease state but describes an array of conditions associated with insult or injury to the brain. While some individuals with TBI recover within a few days or months, others present with persistent symptoms that can cause disability, neuropsychological trauma, and even death. Understanding, diagnosing, and treating TBI is extremely complex for many reasons, including the variable biomechanics of head impact, differences in severity and location of injury, and individual patient characteristics. Because of these confounding factors, the development of reliable diagnostics and targeted treatments for brain injury remains elusive. We argue that the development of effective diagnostic and therapeutic strategies for TBI requires a deep understanding of human neurophysiology at the molecular level and that the framework of multiomics may provide some effective solutions for the diagnosis and treatment of this challenging condition. To this end, we present here a comprehensive review of TBI biomarker candidates from across the multiomic disciplines and compare them with known signatures associated with other neuropsychological conditions, including Alzheimer’s disease and Parkinson’s disease. We believe that this integrated view will facilitate a deeper understanding of the pathophysiology of TBI and its potential links to other neurological diseases.

60 APPLIED LIFE SCIENCES↗

Conformational coupling by trans-phosphorylation in calcium calmodulin dependent kinase II

The calcium calmodulin-dependent protein kinase II (CaMKII) is a dodecameric holoenzyme important for encoding memory. Its activation, triggered by binding of calcium-calmodulin, persists autonomously after calmodulin dissociation. One (receiver) kinase captures and subsequently phosphorylates the regulatory domain peptide of a donor kinase forming a chained dimer as the first stage of autonomous activation. Protein dynamics simulations examined the conformational changes triggered by dimer formation and phosphorylation, aimed to provide a molecular rationale for human mutations that result in learning disabilities. Ensembles generated from X-ray crystal structures were characterized by network centrality and community analysis. Mutual information related collective motions to local fragment dynamics encoded with a structural alphabet. Implicit solvent tCONCOORD conformational ensembles revealed the dynamic architecture of inactive kinase domains was co-opted in the activated dimer but the network hub shifted from the nucleotide binding cleft to the captured peptide. Explicit solvent molecular dynamics (MD) showed nucleotide and substrate binding determinants formed coupled nodes in long-range signal relays between regulatory peptides in the dimer. Strain in the extended captured peptide was balanced by reduced flexibility of the receiver kinase C-lobe core. The relays were organized around a hydrophobic patch between the captured peptide and a key binding helix. The human mutations aligned along the relays. Thus, these mutations could disrupt the allosteric network alternatively, or in addition, to altered binding affinities. Non-binding protein sectors distant from the binding sites mediated the allosteric signalling; providing possible targets for inhibitor design. Phosphorylation of the peptide modulated the dielectric of its binding pocket to strengthen the patch, non-binding sectors, domain interface and temporal correlations between parallel relays. These results provide the molecular details underlying the reported positive kinase cooperativity to enrich the discussion on how autonomous activation by phosphorylation leads to long-term behavioural effects.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Modeling the Potential Effects of New Tobacco Products and Policies. A Dynamic Population Model for Multiple Product Use and Harm

Background Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. Methods and Findings We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use for the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Conclusion Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health outcomes such as morbidity and disability.

59 BASIC BIOLOGICAL SCIENCES↗

2000 Bay Area Travel Survey

In 2000, the San Fransisco Bay Area Metropolitan Transportation Commission launched its fifth travel survey effort in the nine-county Bay Area. More than 15,000 households participated. The survey was an activity-based travel survey that collected information on all in-home and out-of-home activities over a two-day period, including weekday and weekend pursuits. Like the 1990 survey, the 2000 Bay Area Travel Survey also included an additional sample of 3,000 households using Bay Area Rapid Transit. Respondents were asked to report detailed information regarding their travel, including trip locations, mode of transportation, trip start and end times, trip purpose, and trip activities. Demographic variables include gender, age, employment status, occupation, income, education level, ethnicity, as well as whether a respondent held a valid driver's license, was a student, and had a disability.

1Hz data↗

Transcranial Direct Current Stimulation (tDCS) Improves Empathy and Recognition of Facial Emotions Conveying Threat in Adults with Autism Spectrum Disorder (ASD): A Randomized Controlled Pilot Study

Introduction: Empathy is critical for human interactions to become shared and meaningful, and it is facilitated by the expression and processing of facial emotions. Deficits in empathy and facial emotion recognition are associated with individuals with autism spectrum disorder (ASD), with specific concerns over inaccurate recognition of facial emotion expressions conveying a threat. Yet, the number of evidenced interventions for facial emotion recognition and processing (FERP), emotion, and empathy remains limited, particularly for adults with ASD. Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation, may be a promising treatment modality to safely accelerate and/or enhance treatment interventions to increase their efficacy. Methods: This study investigates the effectiveness of FERP, emotion, and empathy treatment interventions paired with tDCS for adults with ASD. Differences in scores on the Empathy Quotient (EQ) and on a FERP test were predicted for verum tDCS when compared to sham. Verum/sham tDCS was randomly assigned in a within-subjects, double-blinded design in adults with ASD without intellectual disability. Results: Verum tDCS significantly improved EQ scores and FERP scores for emotions that conveyed threat. Conclusions: These results suggest the potential for increasing the efficacy of treatment interventions by pairing them with tDCS for individuals with ASD.

59 BASIC BIOLOGICAL SCIENCES↗

State Machine Operation of Complex Systems

Operation of complex systems which depend on one or more other systems with many process variables often operate in more than one state. For each state there may be a variety of parameters of interest, and for each of these, one may require different alarm limits, different archiving needs, and have different critical parameters. Relying on operators to reliably change 10s-1000s of parameters for each system for each state is unreasonable. Not changing these parameters results in alarms being ignored or disabled, critical changes missed, and/or possible data archiving problems. To reliably manage the operation of complex systems, such as cryomodules (CMs), Fermilab is implementing state machines for each CM and an over-arching state machine for the PIP-II superconducting linac (SCL). The state machine transitions and operating parameters are stored/restored to/from a configuration database. Proper implementation of the state machines will not only ensure safe and reliable operation of the CMs, but will help ensure reliable data quality. A description of PIP-II SCL, details of the state machines, and lessons learned from limited use of the state machines in recent CM testing will be discussed.

43 PARTICLE ACCELERATORS↗

Improved Beam Loss Accounting with Fast Data Acquisition (DAQ) Chassis

Identifying the source of beam loss events in the CE-BAF accelerator can be a challenging task. However, with our new prototype system, this task becomes more effi-cient. The system, developed in the fall of 2022, utilizes a dispersive beam position monitor (BPM) and the exist-ing switched electrode electronics BPM hardware. Previ-ously a commercial off-the-shelf data acquisition (DAQ) system was employed to capture BPM wire signals at a sample rate of 20 kS/s. The fast shutdown signal triggered the system, which disables the beam at the injector. Analysis of beam position and energy variation before a beam loss event was used to determine if the beam loss event was associated with an energy transient. The proto-type system, implemented using National Instruments hardware and LabVIEW® software, relied on a software trigger. Manual post-processing was required to ascertain whether the fault was due to an un-tripped cavity with a gradient or phase transient. This work focuses on deploying a Fast DAQ Chassis to monitor BPM hardware in real time and during beam loss events. This system was originally developed and in-stalled in CEBAF to monitor the time-domain RF control signals in the legacy analog RF systems. This technology was leveraged to also monitor BPM signals. As the new system employs a hardware trigger, developing tools to automatically identify faults linked to energy transients unrelated to cavity faults will be straightforward. This paper will discuss the project's initial updates, underlin-ing the crucial role of each member of our team in this achievement

Tiskumara, J.↗

Improving Memory Error Handling Using Linux

As supercomputers continue to get faster and more powerful in the future, they will also have more nodes. If nothing is done, then the amount of memory in supercomputer clusters will soon grow large enough that memory failures will be unmanageable to deal with by manually replacing memory DIMMs. "Improving Memory Error Handling Using Linux" is a process oriented method to solve this problem by using the Linux kernel to disable (offline) faulty memory pages containing bad addresses, preventing them from being used again by a process. The process of offlining memory pages simplifies error handling and results in reducing both hardware and manpower costs required to run Los Alamos National Laboratory (LANL) clusters. This process will be necessary for the future of supercomputing to allow the development of exascale computers. It will not be feasible without memory error handling to manually replace the number of DIMMs that will fail daily on a machine consisting of 32-128 petabytes of memory. Testing reveals the process of offlining memory pages works and is relatively simple to use. As more and more testing is conducted, the entire process will be automated within the high-performance computing (HPC) monitoring software, Zenoss, at LANL.

97 MATHEMATICS AND COMPUTING↗

Hydraulic Capacity of an ADA Compliant Street Drain Grate

Resurfacing of urban roads with concurrent repairs and replacement of sections of curb and sidewalk may require pedestrian ramps that are compliant with the American Disabilities Act (ADA), and when street drains are in close proximity to the walkway, ADA compliant street grates may also be required. The Minnesota Department of Transportation ADA Operations Unit identified a foundry with an available grate that meets ADA requirements. Argonne National Laboratory’s Transportation Research and Analysis Computing Center used full scale three dimensional computational fluid dynamics to determine the performance of the ADA compliant grate and compared it to that of a standard vane grate. Analysis of a parametric set of cases was carried out, including variation in longitudinal, gutter, and cross street slopes and the water spread from the curb. The performance of the grates was characterized by the fraction of the total volume flow approaching the grate from the upstream that was captured by the grate and diverted into the catch basin. The fraction of the total flow entering over the grate from the side and the fraction of flow directly over a grate diverted into the catch basin were also quantities of interest that aid in understanding the differences in performance of the grates. The ADA compliant grate performance lagged that of the vane grate, increasingly so as upstream Reynolds number increased. The major factor leading to the performance difference between the two grates was the fraction of flow directly over the grates that is captured by the grates.

3D CFD↗

10 CFR 830 Major Modification Determination for the Advanced Test Reactor Remote Monitoring and Management Capability

The Advanced Test Reactor (ATR; TRA-670), which is located in the ATR Complex at Idaho National Laboratory, was constructed in the 1960s for the purpose of irradiating reactor fuels and materials. Other irradiation services, such as radioisotope production, are also performed at ATR. While ATR is safely fulfilling current mission requirements, assessments are continuing. These assessments intend to identify areas to provide defense–in-depth and improve safety for ATR. One of the assessments performed by an independent group of nuclear industry experts recommended that a remote accident management capability be provided. The report stated that: “contemporary practice in commercial power reactors is to provide a remote shutdown station or stations to allow shutdown of the reactor and management of long-term cooling of the reactor (i.e., management of reactivity, inventory, and cooling) should the main control room be disabled (e.g., due to a fire in the control room or affecting the control room).” This project will install remote reactor monitoring and management capabilities for ATR. Remote capabilities will allow for post scram reactor management and monitoring in the event the main Reactor Control Room (RCR) must be evacuated.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗