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DOE OSTI2014

DNA cleavage enzymes for treatment of persistent viral infections: Recent advances and the pathway forward

Treatment for most persistent viral infections consists of palliative drug options rather than curative approaches. This is often because long-lasting viral DNA in infected cells is not affected by current antivirals, providing a source for viral persistence and reactivation. Targeting latent viral DNA itself could therefore provide a basis for novel curative strategies. DNA cleavage enzymes can be used to induce targeted mutagenesis of specific genes, including those of exogenous viruses. Although initial in vitro and even in vivo studies have been carried out using DNA cleavage enzymes targeting various viruses, many questions still remain concerning the feasibility of these strategies as they transition into preclinical research. Here, we review the most recent findings on DNA cleavage enzymes for human viral infections, consider the most relevant animal models for several human viral infections, and address issues regarding safety and enzyme delivery. Results from well-designed in vivo studies will ideally provide answers to the most urgent remaining questions, and allow continued progress toward clinical application. - Highlights: • Recent in vitro and in vivo results for DNA cleavage enzymes targeting persistent viral infections. • Analysis of the best animal models for testing enzymes for HBV, HSV, HIV and HPV. • Challenges facing in vivo delivery of therapeutic enzymes for persistent viral infections. • Safety issues to be addressed with proper animal studies.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Shape-persistent ladder molecules exhibit nanogap-independent conductance in single-molecule junctions

Molecular electronic devices require precise control over the flow of current in single molecules. However, the electron transport properties of single molecules critically depend on dynamic molecular conformations in nanoscale junctions. Here, in this work, we report a unique strategy for controlling molecular conductance using shape-persistent molecules. Chemically diverse, charged ladder molecules, synthesized via a one-pot multicomponent ladderization strategy, show a molecular conductance (d[log( G/G 0 )]/d x ≈ -0.1 nm -1 ) that is nearly independent of junction displacement, in stark contrast to the nanogap-dependent conductance (d[log( G/G 0 )]/d x ≈ -7 nm -1 ) observed for non-ladder analogues. Ladder molecules show an unusually narrow distribution of molecular conductance during dynamic junction displacement, which is attributed to the shape-persistent backbone and restricted rotation of terminal anchor groups. These principles are further extended to a butterfly-like molecule, thereby demonstrating the strategy's generality for achieving gap-independent conductance. Overall, our work provides important avenues for controlling molecular conductance using shape-persistent molecules. Achieving robust and controllable conductance in single-molecule junctions is challenging due to the dynamic nature of molecular conformations that fluctuate over operational timescales. A strategy using shape-persistent molecules has now been developed that demonstrates nearly junction-displacement-independent conductance, providing a stable solution for single-molecule electronic properties.

molecular electronics↗

DOE OSTI2021

Persistent meanders and eddies lead to quasi-steady Lagrangian transport patterns in a weak western boundary current

The Brazil Current (BC) is a weak western boundary current flowing along the Southwestern Atlantic Ocean. It is frequently described as a flow with intense mesoscale activity and relatively low volume transport between 5.0 and 10.0 Sv. We use a 13-year eddy-resolving primitive-equation simulation to show that the presence of persistent meanders and eddies leads to characteristic quasi-steady Lagrangian transport patterns, aptly extracted through climatological Lagrangian Coherent Structures (cLCS). The cLCS position the surface expression of the BC core along the 2000-m isobath, in excellent visual agreement with high resolution satellite sea-surface temperature and the model Eulerian mean velocity. The cLCS deformation pattern also responds to zonally persistent cross-shelf SSH transition from positive (high) values near coastline to low (negative) values between 200- and 2000-m and back to positive (high) offshore from the 2000-m isobath. Zonally-paired cyclonic and anticyclonic structures are embedded in this transition, also causing the cLCS to deform into chevrons. An efficient transport barrier is identified close to the 200-m isobath confirmed by limited inshore movement of drogued drifters and accurately indicated by an along slope maxima of climatological strength of attraction. We also show that the persistent cyclonic and anticyclonic structures may induce localized cross-shelf transport. Regions of low climatological strength of attraction coincide with large shelves and with stagnant synthetic trajectories. We also show that cLCS accurately depict trajectories initiated at the location of Chevron’s spill (November 2011) as compared to synthetic and satellite-tracked trajectories, and the outline of the oil from that accident. There is also an agreement between the large-scale oil slicks reaching the Brazilian beaches (from August 2019 to February 2020) and the strength of climatological attraction at the coast. Our work also clarifies the influence of persistent mesoscale structures on the regional circulation. The identification and quantitative description of climatological Lagrangian coherent structures is expected to improve the effectiveness of future emergency response to oil spills, contingency planning, rescue operations, larval and fish connectivity assessment, drifter launch strategies, waste pollutant and marine debris dispersion and destination.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2015

Evidence for enhanced persistent emission during sub-eddington thermonuclear bursts

In a recent paper we found evidence for an increase in the accretion rate during photospheric radius expansion bursts, quantified by a variable normalization factor f{sub a} on the preburst persistent emission. Here we follow this result up on a much larger sample of 1759 type I X-ray bursts from 56 sources. We show that the variable persistent flux method provides improvements in the quality of spectral fits for type I bursts, whether or not they reach the Eddington luminosity. The new approach has an estimated Bayes factor of 64 improvement over the standard method, and we recommend that the procedure be adopted as standard for analyzing type I bursts. We show evidence that the remaining discrepancies to a formally consistent spectral model are due to the burst component deviating significantly from a blackbody, rather than variations in the spectral shape of the persistent emission component. In bursts that do not show radius expansion, the persistent emission enhancement does not exceed 37% of the Eddington flux. We use this observation to constrain the Eddington flux of sources for which F{sub Edd} has not been directly measured.

79 ASTRONOMY AND ASTROPHYSICS↗

DOE OSTI2020

Persistent Memory Object Storage and Indexing for Scientific Computing

This paper presents Mosiqs, a persistent memory object storage framework with metadata indexing and querying for scientific computing. We design Mosiqs based on the key idea that memory objects on shared PM pool can live beyond the application lifetime and can become the sharing currency for applications and scientists. Mosiqs provides an aggregate memory pool atop an array of persistent memory devices to store and access memory objects. Mosiqs uses a lightweight persistent memory key-value store to manage the metadata of memory objects such as persistent pointer mappings, which enables memory object sharing for effective scientific collaborations. Mosiqs is implemented atop PMDK. We evaluate the proposed approach on many-core server with an array of real PM devices. The preliminary evaluation confirms a 100% improvement for write and 30% in read performance against a PM-aware file system approach.

Khan, Awais↗

DOE OSTI2015

Validation of Finite-Element Models of Persistent-Current Effects in Nb 3 Sn Accelerator Magnets

Persistent magnetization currents are induced in superconducting filaments during the current ramping in magnets. The resulting perturbation to the design magnetic field leads to field quality degradation, in particular at low field where the effect is stronger relative to the main field. The effects observed in NbTi accelerator magnets were reproduced well with the critical-state model. However, this approach becomes less accurate for the calculation of the persistent-current effects observed in Nb 3 Sn accelerator magnets. Here a finite-element method based on the measured strand magnetization is validated against three state-of-art Nb3Sn accelerator magnets featuring different subelement diameters, critical currents, magnet designs and measurement temperatures. The temperature dependence of the persistent-current effects is reproduced. Based on the validated model, the impact of conductor design on the persistent current effects is discussed. The performance, limitations and possible improvements of the approach are also discussed.

36 MATERIALS SCIENCE↗

DOE OSTI2018

Persistent Octrees for Parallel Mesh Refinement Through Non-Volatile Byte-Addressable Memory

We report that octree-based mesh adaptation has enabled simulations of complex physical phenomena. Existing meshing algorithms were proposed with the assumption that computer memory is volatile. Consequently, for failure recovery, the in-core algorithms need to save memory states as snapshots with slow file I/Os. The out-of-core algorithms store octants on disks for persistence. However, neither of them was designed to leverage unique characteristics of non-volatile byte-addressable memory (NVBM). In this paper, we propose a novel data structure Distributed Persistent Merged octree (DPM-octree) for both meshing and in-memory storage of persistent octrees using NVBM. It is a multi-version data structure and can recover from failures using its earlier persistent version stored in NVBM. In addition, we design a feature-directed sampling approach to help dynamically transform the DPM-octree layout for reducing NVBM-induced memory write latency. DPM-octree uses parity trees which are created using erasure coding and stored in NVBM to support low-latency in-memory octant recovery after data loss. DPM-octree has been successfully integrated with Gerris software for simulation of fluid dynamics. Finally, our experimental results with real-world scientific workloads show that DPM-octree scales up to 1.1 billion mesh elements with 1000 processors on the Titan supercomputer.

97 MATHEMATICS AND COMPUTING↗

DOE OSTI2025

Optimizing Management of Persistent Data Structures in High-Performance Analytics

Large-scale data analytics workflows ingest massive input data into various data structures, including graphs and key-value datastores. These data structures undergo multiple transformations and computations and are typically reused in incremental and iterative analytics workflows. Persisting in-memory views of these data structures enables reusing them beyond the scope of a single program run while avoiding repetitive raw data ingestion overheads. Memory-mapped I/O enables persisting in-memory data structures without data serialization and deserialization overheads. However, memory-mapped I/O lacks the key feature of persisting consistent snapshots of these data structures for incremental ingestion and processing. The obstacles to efficient virtual memory snapshots using memory-mapped I/O include background writebacks outside the application’s control, and the significantly high storage footprint of such snapshots. To address these limitations, we present Privateer, a memory and storage management tool that enables storage-efficient virtual memory snapshotting while also optimizing snapshot I/O performance. Here, we integrated Privateer into Metall, a state-of-the-art persistent memory allocator for C++, and the Lightning Memory-Mapped Database (LMDB), a widely-used key-value datastore in data analytics and machine learning. Privateer optimized application performance by 1.22× when storing data structure snapshots to node-local storage, and up to 16.7× when storing snapshots to a parallel file system. Privateer also optimizes storage efficiency of incremental data structure snapshots by up to 11× using data deduplication and compression.

Computer science↗

DOE OSTI2024

Persistent urban heat

Urban surface and near-surface air temperatures are known to be often higher than their rural counterparts, a phenomenon now labeled as the urban heat island effect. However, whether the elevated urban temperatures are more persistent than rural temperatures at timescales commensurate to heat waves has not been addressed despite its importance for human health. Combining numerical simulations by a global climate model with a surface energy balance theory, it is demonstrated here that urban surface and near-surface air temperatures are significantly more persistent than their rural counterparts in cities dominated by impervious materials with large thermal inertia. Further use of these materials will result in even stronger urban temperature persistence, especially for tropical cities. The present findings help pinpoint mitigation strategies that can simultaneously ameliorate the larger magnitude and stronger persistence of urban temperatures.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2012

Persistent heap Management library

PERM is a C library for persistent heap management and is intended for use with a dynamic-memory allocator (e.g. malloc, free). The PERM memory allocator replaces the standard C dynamic memory allocation functions with compatible versions that provide persistent memory to application programs. Memory allocated with the PERM allocatory will persist between program invocations after a call to a checkpoint function. This function essentially saves the state of the heap and registered global variables to a file which may reside in flash memory or other node local storage. A few other functions are also provided by the library to manage checkpoint files. Global variables in an application can be marked persistent and be included in a checkpoint by using a compiler attribute defined as PERM. The PERM checkpoint methof is not dependent on the programming model ans works with distributed memory or shared memory programs.

Source record↗

DOE OSTI2020

Long-term persistence of infectious Zika virus: Inflammation and behavioral sequela in mice

The neurodevelopmental defects associated with ZIKV infections early in pregnancy are well documented, however the potential defects and long-term consequences associated with milder infections in late pregnancy and perinatal period are less well understood. To model these, we challenged 1 day old (P1) immunocompetent C57BL/6 mice with ZIKV. The animals developed a transient neurological syndrome including unsteady gait, kinetic tremors, severe ataxia and seizures 10–15 days post-infection (dpi) but symptoms subsided after a week, and most animals survived. Despite apparent recovery, MRI of convalescent mice show reduced cerebellar volume that correlates with altered coordination and motor function as well as hyperactivity and impulsivity. Persistent mRNA levels of pro-inflammatory genes including Cd80 , Il-1α , and Ifn-γ together with Cd3 , Cd8 and perforin ( PrfA) , suggested persistence of low-grade inflammation. Surprisingly, the brain parenchyma of convalescent mice harbor multiple small discrete foci with viral antigen, active apoptotic processes in neurons, and cellular infiltrates, surrounded by activated astrocytes and microglia as late as 1-year post-infection. Detection of negative-sense strand viral RNA and isolation of infectious virus derived from these convalescent mice by blinded passage in Vero cells confirmed long-term persistence of replicating ZIKV in CNS of convalescent mice. Although the infection appears to persist in defined reservoirs within CNS, the resulting inflammation could increase the risk of neurodegenerative disorders. This raises concern regarding possible long-term effects in asymptomatic children exposed to the virus and suggests that long-term neurological and behavioral monitoring as well as anti-viral treatment to clear virus from the CNS may be useful in patients exposed to ZIKV at an early age.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

Toward a persistent event-streaming system for high-performance computing applications

High-performance computing (HPC) applications have traditionally relied on parallel file systems and file transfer services to manage data movement and storage. Alternative approaches have been proposed that use direct communications between application components, trading persistence and fault tolerance for speed. Event-driven architectures, as popularized in enterprise contexts, present a compelling middle ground, avoiding the performance cost and API constraints of parallel file systems while retaining persistence and offering impedance matching between application components. However, adapting streaming frameworks to HPC workloads requires addressing challenges unique to HPC systems. This paper investigates the potential for a streaming framework designed for HPC infrastructures and use cases. We introduce Mofka, a persistent event-streaming framework designed specifically for HPC environments. Mofka combines the capabilities of a traditional streaming service with optimizations tailored to the HPC context, such as support for massively multicore nodes, efficient scaling for large producer-consumer workflows, RDMA-enabled high-performance network communications, specialized network fabrics with multiple links per node, and efficient handling of large scientific data payloads. Built using the Mochi suite of HPC data service components, Mofka provides a lightweight, modular, and high-performance solution for persistent streaming in HPC systems. We present the architecture of Mofka and evaluate its performance against Kafka and Redpanda using benchmarks on diverse platforms, including Argonne's Polaris and Oak Ridge's Frontier supercomputers, showing up to 8× improvement in throughput in some scenarios. We then demonstrate its utility in several real-world applications: a tomographic reconstruction pipeline, a workflow for the discovery of metal-organic frameworks for carbon capture, and the instrumentation of Dask workflows for provenance tracking and performance analysis.

HPC↗

DOE OSTI2021

Evaluating State Space Discovery by Persistent Cohomology in the Spatial Representation System

Persistent cohomology is a powerful technique for discovering topological structure in data. Strategies for its use in neuroscience are still undergoing development. We comprehensively and rigorously assess its performance in simulated neural recordings of the brain's spatial representation system. Grid, head direction, and conjunctive cell populations each span low-dimensional topological structures embedded in high-dimensional neural activity space. We evaluate the ability for persistent cohomology to discover these structures for different dataset dimensions, variations in spatial tuning, and forms of noise. We quantify its ability to decode simulated animal trajectories contained within these topological structures. We also identify regimes under which mixtures of populations form product topologies that can be detected. Our results reveal how dataset parameters affect the success of topological discovery and suggest principles for applying persistent cohomology, as well as persistent homology, to experimental neural recordings.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

Lack of Transmission of Foot-and-Mouth Disease Virus From Persistently Infected Cattle to Naïve Cattle Under Field Conditions in Vietnam

Foot-and-mouth disease (FMD), caused by FMD virus (FMDV; Aphthovirus, Picornaviridae), is a highly contagious and economically important disease of clovenhoofed domestic livestock and wildlife species worldwide. Subsequent to the clinical phase of FMD, a large proportion of FMDV-infected ruminants become persistently infected carriers, defined by detection of FMDV in oropharyngeal fluid (OPF) samples 28 days or more post-infection. The goal of this prospective study was to characterize the FMD carrier state in cattle subsequent to natural infection under typical husbandry practices in Vietnam. Ten persistently infected cattle on eight farms in the Long An province in southern Vietnam were monitored by monthly screening of serum and oropharyngeal fluid samples for 12 months. To assess transmission from FMDV carriers, 16 naïve cattle were intentionally brought into direct contact with the persistently infected animals for 6 months, and were monitored by clinical and laboratory methods. The restricted mean duration of the FMD carrier state was 27.7 months, and the rate of decrease of the proportion of carrier animals was 0.03 per month. There was no evidence of transmission to naïve animals throughout the study period. Additionally, there was no detection of FMDV infection or seroconversion in three calves born to carrier animals during the study. The force of infection for carrier-to-contact transmission was 0 per month, with upper 95% confidence limit of 0.064 per month. Phylogenetic analysis of viral protein 1 (VP1) coding sequences obtained from carriers indicated that all viruses recovered in this study belonged to the O/ME-SA/PanAsia lineage, and grouped phylogenetically with temporally and geographically related viruses. Analysis of within-host evolution of FMDV, based upon full-length open reading frame sequences recovered from consecutive samples from one animal, indicated that most of the nonsynonymous changes occurred in Lpro, VP2, and VP3 protein coding regions. This study suggests that the duration of FMDV persistent infection in cattle may be longer than previously recognized, but the risk of transmission is low. Additional novel insights are provided into within-host viral evolution under natural conditions in an endemic setting.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS1979

Persistent emission from X-ray burst sources and the nature of galactic bulge X-ray sources

Intrinsic persistent emission from galactic bulge X-ray sources and the ratio of the average persistent X-ray luminosity to the time-averaged burst luminosity associated with Type I burst sources are discussed in the light of the thermonuclear flash model of X-ray burst emission. Values of the ratio between average persistent luminosity and time-averaged burst luminosity for a large collection of SAS 3 sources are presented to confirm the predictions of the burst model of thermonuclear flashes in freshly accreted matter on a neutron star. The model also predicts a critical value of the persistent accretion rate, below which bursts can occur. It is suggested that the galactic bulge X-ray sources represent neutron stars undergoing accretion, with burst sources accounting for a subset in which the accretion rate is below the critical value.

Van Paradijs, J.↗

NASA NTRS1987

Statistics and dynamics of persistent anomalies

Persistent anomalies with recurrent spatial patterns play an important role in the atmosphere's low-frequency variability. A connection between statistical and dynamical methods of description and prediction of persistent anomalies is established by computing and analyzing the empirical orthogonal functions (EOFs) in a simple deterministic model, on the one hand, and in Southern Hemisphere geopotential heights, on the other. The dynamical model is governed by the fully nonlinear, equivalent-barotropic vorticity equation on the sphere, with simplified forcing, dissipation and topography. The Southern Hemisphere data consist in gridded daily maps of 500 mb heights from June 1972 to July 1983. Two types of persistent anomalies appear in this time series, both having a strong wavenumber-three component; they differ by the value of the constant phase of this wave and by the strength of the wavenumber-one component. The first two EOFs bear a striking resemblance to these two patterns. It is concluded that the dynamical interpretation of EOFs is their pointing from the time mean to the most populated regions of the system's phase space. Pursuing this interpretation, a Markov-chain formulation of transitions from one persistent anomaly regime to another is introduced, and the implications for long-range forecasting are discussed.

Mo, Kingtse C.↗

NASA NTRS1993

Unusual features in the persistent emission of the Rapid Burster

Several distinct features in the persistent X-ray emission after long (greater than 30 s) type II bursts from the Rapid Burster were discovered in August 1985. A specific pattern characterized by a 'hump' was observed in the early portion of the persistent emission after type II bursts with integrated fluxes less than about 4.8 x 10 exp -6 erg/sq cm. This hump which typically lasts about 200 s is almost never observed after bursts with fluences greater than this value. The emission during the hump is found to be always harder than the average persistent emission. Quasi-periodic oscillations with frequencies of about 40 mHz observed in 10 cases occur exclusively during a hump. The persistent emission also exhibited sharp 'glitches' and small 'bumps' lasting about 20-100 s. The glitches always occurred at the same phase in the intervals between bursts. In seven cases the glitches were followed by a bump.

Lubin, Lori M.↗

NASA NTRS2010

Diagnosing Intermittent and Persistent Faults using Static Bayesian Networks

Both intermittent and persistent faults may occur in a wide range of systems. We present in this paper the introduction of intermittent fault handling techniques into ProDiagnose, an algorithm that previously only handled persistent faults. We discuss novel algorithmic techniques as well as how our static Bayesian networks help diagnose, in an integrated manner, a range of intermittent and persistent faults. Through experiments with data from the ADAPT electrical power system test bed, generated as part of the Second International Diagnostic Competition (DXC-10), we show that this novel variant of ProDiagnose diagnoses intermittent faults accurately and quickly, while maintaining strong performance on persistent faults.

Megshoel, Ole Jakob↗