STE Highlights, March 2020

Bioscience

Understanding “persister cells” pushes frontiers of infectious disease management

Some infectious bacterial cells survive antibiotic treatment at a small rate of <1%, displaying antibiotic resistance that is not inherited, meaning genetic mutations are not the reason they are persisting. Rather, these persister cells are genetically identical to the bacterial cells that routinely die from antibiotic treatment. So, how are they persisting?

In a recent study by Los Alamos bioscientists, persister cells of Burkholderia thailandensis were investigated to better understand how these cells are phenotypically changing in response to their environment in order to survive. Although persister cells do not pass their tolerance characteristic to their progeny, they do create a reservoir of surviving cells that can lead to the evolution of resistance mutations. Learning more about these cells will help prevent chronic infection.

Persister cells strategically turn genes on and off

The researchers found that when antibiotics were administered to the cells, the persisters activated a specific gene cluster that produces natural products with HDAC-inhibitory effects to regulate bacterial DNA replication and possibly host immune responses. Persisters also turn on genes that enable them to use fatty acid stores for energy and building blocks for membrane lipid structures. These are two examples of commonality among persister cells when faced with environmental stress, but there can also be a great deal of variability.  

“Collectively, our results support a model in which bacterial persisters exhibit an outwardly dormant physiology but sustain active metabolic processes that are required to maintain persistence,” said Sofiya Micheva-Viteva, Los Alamos bioscientist.

The identification of genes most important to bacterial persistence could lead to the development of anti-persistence therapeutics to combat infectious disease.

Funding and mission

The research was funded by Defense Threat Reduction Agency (DTRA) of the U.S. Department of Defense (DoD). The work supports the Laboratory’s Global Security mission area and the Science of Signatures capability pillar.

Reference: Sofiya N. Micheva-Viteva, Migun Shakya, Samantha H. Adikari, Cheryl D. Gleasner, Nileena Velappan, Judith R. Mourant, Patrick S. G. Chain, Elizabeth Hong-Geller. “A Gene Cluster That Encodes Histone Deacetylase Inhibitors Contributes to Bacterial Persistence and Antibiotic Tolerance in Burkholderia thailandensis.” mSystems. 11 Feb 2020. DOI: 10.1128/mSystems.00609-19

Technical contact: Sofiya N. Micheva-Viteva

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Capability Enhancement

Functional data analysis applied to new weapons physics tools

Incorporating cutting-edge science and technology into our weapon designs is essential to national security. The most recent incorporation comes in the form of functional data analysis. The premise is to free up the weapons designer from tasks a computer can perform just as well, so that the designer can focus on human-required decision-making—seeing the big picture in order to guide the future of weapons design. It is a streamlining and optimization of design tasks.

Functional data analysis is being added to LANL’s recent successful modernization of weapons design tools. These new tools extended existing capabilities (focused on classic weapon designs currently in the stockpile) to non-canonical weapons designs and optimization of design for a weapons full lifecycle.

"These tools allow our engineers and scientists to experience every part of a weapon’s lifecycle; this is really valuable in the event we need to design a weapon from scratch,” said Matt Tucker, Weapon Stockpile Modernization Division.

Modernization is a must

Weapon design policy has had ups and downs over the decades, with a hiatus on new design concepts since the start of the Stockpile Stewardship Program (except for the Reliable Replacement Warhead and some lower-level paper studies). During that time, generational turnover started occurring in high numbers, resulting in a new workforce that had never fully designed a weapon from start to finish. It was a vulnerability in our defense posture.

This was addressed for the first time in 2016 with the Stockpile Responsiveness Program, which included a congressional mandate “to identify, sustain, enhance, integrate, and continually exercise all capabilities required to conceptualize, study, design, develop, engineer, certify, produce, and deploy nuclear weapons.”  Then, the 2018 Nuclear Posture Review called for modernization, and Los Alamos followed through on both fronts—modernizing weapon design from start to finish.

"We tested our new design tools in July 2019 with an actual experiment: a hydro of a non-canonical design,” Tucker said. "Hydros use surrogate materials to safely test weapons designs. “It confirmed that we were able to predict the behavior very well.”

However, there were also instances when the codes did not work as well as the scientists had expected. But as Tucker explained, it’s important to understand where you can trust your tools and where you can’t. That alone is valuable information.

The production complexes have changed

Another important goal of modernizing our design tools is to improve our ability to actually manufacture the weapons. Production complexes have changed since the time of classic designs, which means it’s becoming more difficult to bring those designs to life as a real weapon. Modernizing the codes will help make new weapons more manufacturable.

The new design tools developed through this project were briefed to the National Nuclear Security Administration (NNSA). The proven success spurred the Design for Manufacture Program that is now in place.

Optimizing new tools even further

These new tools can be improved. Freeing up designers from tasks that could be performed by a computer is one such optimization.

To get to that point, statistical methods have to be applied to the choices designers make. The computer has to learn about these choices and when to make them. Data has become increasingly complex over the years, including complicated curves and images. Until now, that meant that learning algorithms relied on very large datasets for learning. This new functional data analysis removes that dependency, reducing the parameter search space for learning algorithms.

To put this method in place, scientists in Computer, Computational, and Statistical Sciences (CCS) Division observed some top weapons design engineers at Los Alamos during design decision-making. These decisions became the dataset from which the computer model was built.

This method is a cutting-edge modernization of current weapon design. It simplifies and streamlines tasks and complexity so that more can be accomplished rapidly and accurately.

Funding and mission

This research was funded by a LANL Laboratory Directed Research and Development (LDRD) award. The work supports the Laboratory’s Nuclear Deterrence mission area and the Weapons Systems capability pillar.

Reference: Joanne Wendelberger and Claire Bowen (Urban Institute). “Iterative Modeling with Functional Data.” Invited presentation, 2019 Fall Technical Conference. Gaithersburg, Maryland. September 25–27, 2019.

Claire Bowen (Urban Institute) and Joanne Wendelberger. “Iterative Design with Humans-In-The-Loop for Functional Data Analysis.” Joint Statistical Meetings. Denver, Colorado. July 28–August 1, 2019.

Technical contacts: Matt Tucker and Joanne Wendelberger

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Earth and Environmental Sciences

The greenhouse that supports our nation: From biofuel to environmental research

Los Alamos National Laboratory recently unveiled a remodeled greenhouse to further support national research in chemistry, earth, and life sciences. Led by the Earth and Environmental Sciences (EES) Division, the significant improvements were made to the existing but aging property. These improvements further boost LANL’s contributions to the areas of nuclear nonproliferation, food security, and forest mortality as well as the understanding of effects of climate change on vegetation.

Beginning in 2019, renovations to the 900-square-foot greenhouse aimed to make the facility viable for year-round experimental research. Improvements include new glass panels, infrastructure changes for sanitation, and significant modernization of temperature controls. Completing the upgrades expands Los Alamos’ capabilities, supporting a variety of new research.

Expanded Research Capabilities

Sanna Sevanto, EES Atmosphere, Climate, and Ecosystem Science Team Leader, is currently managing the greenhouse. In one example of the expanded research capabilities at the facility, Sevanto and Bioscience Division’s John Dunbar are co-leading a Laboratory Directed Research and Development (LDRD)-funded team aiming to harness plant-microbiome interactions in support of food and biofuel security.

The greenhouse is also empowering two EES Division New Mexico Small Business Association projects: one investigating the environmental effects of burial stones on vegetation and another studying impacts of microbial soil amendments on crop growth to support food security. In addition, Sevanto and Shawn Starkenburg are leading a Center for Space and Earth Science (CSES) student project developing methods for cellular-level genetics studies in plants.

The greenhouse is also supporting a multi-division project investigating plant microbial response to radiation and chemical stressors (Principal Investigator Helen Cui, B Division; partners Scott Twary of Biosciences; Sevanto; and Chemistry Division’s Chris Yeager).

Sevanto and colleagues aim to increase greenhouse capabilities even further, including modifying some of the infrastructure for dedicated radiological projects. Several program efforts across the Chemistry, Earth, and Life Sciences (CELS) Divisions shed light on the potential of such work, and program development efforts in these divisions and the Nuclear Engineering and Nonproliferation Division would benefit from the increased capability.

Funding and mission

The greenhouse was funded by the CELS Associate Laboratory Directorate. The associated research supports the Laboratory’s Energy Security mission area and the Complex Natural and Engineered Systems capability pillar.

Technical Contact: Sanna Sevanto

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Explosive Science and Shock Physics

New class of switchable explosive could revolutionize explosive safety

Los Alamos researchers and colleagues from the University of Pennsylvania, by combining the fields of inorganic coordination chemistry and explosive science, have documented the very first explosive spin-crossover complex that can transition from a safer “less sensitive phase” to an active “more sensitive phase.” The switching mechanism is reversible with respect to impact sensitivity. This discovery sets the groundwork to revolutionize the safety of explosives.

“Spin crossover is a property that has been studied for some time, especially in Fe(II) heterocyclic compounds, but no one has reported it in an explosive material nor has anyone correlated it with switchable sensitivity in an explosive,” said Jackie Veauthier, Deputy Group Leader of Inorganic Isotope and Actinide Chemistry.

Spin crossover means the material has two stable electronic spin states (rather than just one) and the material can transition, or switch, between the states. These transitions result in molecular changes (e.g., volume, enthalpy, and bond lengths), which naturally results in one of the states being less sensitive and the other more sensitive. This is an ideal characteristic to hone in explosives.

A spin-crossover material and an explosive

The researchers focused on a particular complex: [Fe(Htrz)₃]_n[ClO₄]_2n. This complex is a known spin-crossover material, but it had not been reported as an explosive. It turns out it’s both.

In the current study, the complex’s magnetic properties and variable temperature impact sensitivity were measured. For the latter, a new jacketed collar was designed specifically for the test. Density Functional Theory was used to understand how the structural and energy changes that occur upon spin transition correlate to changes in sensitivity. The results indicate that [Fe(Htrz)₃]_n[ClO₄]_2n is indeed an explosive and, therefore, the first impact-sensitive switchable explosive to be documented.

The spin transition required for the switching mechanism can occur in response to both thermal and non-thermal stimuli, including magnetic fields, pressures, and irradiation with light. The complex also passed an aging test, which is an indicator of long-term stability.

Beyond this correlation

Spin-crossover materials are popular, and more are being created all the time, mostly for application in electronic devices such as sensors and displays. Many of these inorganic metal coordination spin-crossover complexes have energy-dense, nitrogen-rich ligands that can be derivatized and optimized to have explosive properties. The team is currently working to prepare new samples to be tested as possible switchable explosives.

“The goal is to increase the gap between less sensitive and more sensitive while still being able to switch states, with an ultimate goal of preparing a material that can be switched between an insensitive to a sensitive state,” said Veauthier. This is an ideal method to further enhance the safety of explosives.

Explosives are used by military soldiers, miners, and construction workers. Safer explosives translates to fewer fatal accidents.

Funding and mission

This research was funded by a LANL Laboratory Directed Research and Development (LDRD) award. This research used resources provided by the LANL Institutional Computing (IC) Program. The work supports the Laboratory’s Nuclear Deterrence mission area and the Materials for the Future capability pillar.

Reference: Thuy-Ai D. Nguyen, Jacqueline M. Veauthier, Gary F. Angles-Tamayo, David E. Chavez, Ekaterina Lapsheva (U. of Pennsylvania), Thomas W. Myers, Tammie R. Nelson, Eric J. Schelter (U. of Pennsylvania). “Correlating Mechanical Sensitivity with Spin Transition in the Explosive Spin Crossover Complex [Fe(Htrz)₃]_n[ClO₄]_2n.” JACS. February 2020. https://doi.org/10.1021/jacs.9b13835

Technical contacts: Jacqueline Veauthier, Thuy-Ai Nguyen, and David E. Chavez

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Materials Physics and Applications

First restartable rocket motor to maneuver satellites in space

Los Alamos researchers developed the first-ever restartable motor for solid rockets. With the patented design, the scientists and engineers were able to demonstrate restarting the motor at least six times in succession. All other solid rocket motors in use are a “one and done” scenario for maneuvering in space.

This new technology will help solve the increasing problem of space traffic, as more small satellites (cubesats) are sent into orbit. The restartable motor will enable satellites to maneuver around other orbiting objects on short notice, preventing costly space crashes.

A second high-priority defense application of this invention is missile maneuvering.

“Solid fuel-propelled missiles equipped with this technology will be able to perform multiple independent burns that will allow them to reach their targets through atypical non-ballistic flight paths,” said Ian Shelburne of High-Energy Science and Technology (M-7).

Multi-burn solid rocket system

Solid rockets are an attractive choice because they are simple, low-cost, and scalable. However, traditional solid rockets are limited to one burn of fixed impulse for maneuvering. The Los Alamos researchers addressed this limitation by designing a multi-burn solid rocket system coupled with a re-usable ignition system.

“We developed an aerospike nozzle at Los Alamos with an actuated cowl,” said Nicholas Dallmann, lead research engineer (MPA-Quantum). “Once a burn has achieved the desired velocity change, the cowl would rapidly open, decompressing the chamber and extinguishing the burn. When another burn of the rocket is needed, the cowl is reset to its original position.”

Solid rockets aren’t the answer to everything, but this engineering enhancement greatly expands their usefulness. It will also help limit the amount of space debris that threatens national security satellites and instrumentation.

Electrolysis ignition is safe and environmentally sound

The Los Alamos researchers designed a safe, reusable ignition system that relies on the electrolysis of water instead of volatile pressurized chemicals. This enhances the safety of material handling as well as the safety of any flight crew and the environment.

The water is separated into hydrogen and oxygen through electrolysis. These are sent to the combustion chamber, where a spark ignites the gas. This can occur over and over for multiple burns. Re-ignition is one of the key features of this technology.

This system is also stable for very long periods (multiple decades), which is ideal for the lifetime of space flight or storage of a missile.

Funding and mission

This research was funded by a LANL Laboratory Directed Research and Development award. The work supports the Laboratory’s Global Security mission area and the Complex Natural and Engineered Systems capability pillar.

Technical contact: Nicholas Dallmann and Ian Shelburne

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Proposal Call

Proposal call: Los Alamos cutting-edge research to combat COVID-19

A proposal call for research that responds to the COVID-19 outbreak has been issued by the Laboratory Directed Research and Development (LDRD) Program. Details of requirements were presented in a virtual town hall meeting on March 18, and all proposals are due by Monday, March 30.

Proposals will focus on three main research areas of the COVID-19 virus:

• therapeutics/vaccines,
• diagnostics,
• and decision support and infrastructure management (including disease modeling and epidemiology).

Proposals will be selected and immediately funded based upon the realistic capabilities the research can offer the public in combatting this virus.

Los Alamos offers expertise and infrastructure

Los Alamos Director Thom Mason appointed Patrick Fitch, Associate Laboratory Director for Chemical, Earth, and Life Sciences, as the LANL Special Office for COVID-19 lead. Fitch has supported previous outbreak response activities, such as for SARS, and takes that experience into his current leadership role.

Los Alamos is home to some of the world’s top scientists and engineers. Within the past few years, Los Alamos scientists under Fitch have delivered the first 3D image of RNA, a new platform for rapid genomic-sequence data analysis, and a novel HIV vaccine.

“The Lab’s ST&E capabilities are well-positioned to have an impact on COVID-19 locally and nationally, and there are many staff members that are already going above and beyond to help,” Fitch said. As of late March, these impact areas include

• Modeling in Support of Response
• Laboratory Testing Options
• Manufacturing
• Application of AI and Machine Learning
• Medical Countermeasures
• High Performance Computing

17 Labs in all—answers are coming

Los Alamos proposals can suggest partnerships with industry or other national laboratories. Fitch is the point of contact for guidelines and clearance on all such work. These partnerships will bolster the Los Alamos efforts and enhance capabilities to deliver needed solutions quickly.

These partnerships are especially encouraged by the Department of Energy’s Office of Science Director Chris Falls, who spoke to the idea of collaborative efforts. He cited the strengths as “our ability to do big science — lots of people working on a problem. They know how to work together; they know how to share information and data.”

The goal is to promote a synergistic effect—combining the top resources from each laboratory to achieve better solutions, such as improved virus testing or development of an effective vaccine.

Funding and mission

The proposals will be funded by the Los Alamos LDRD Program. The work supports the Laboratory’s Global Security mission area.

Technical contact: Pat Fitch

Seaborg Institute rapid response call for actinide science

The Los Alamos Seaborg Institute is calling for proposals to expand capabilities in actinide science. All proposals are due by April 6, 2020, and research must be completed in fiscal year 2020, by September 30.

Los Alamos is the Plutonium Center of Excellence in the United States. The Seaborg Institute works in combination with the Los Alamos Plutonium Facility to promote cutting-edge research in actinide science, technology, and manufacturing.

Proposal call details

This rapid response call is specifically addressing the Laboratory’s 2020 Agenda. Although unclassified proposals are within the scope of the call, classified proposals that push the boundaries in a high-risk, high-reward manner are recommended.

Specific examples of proposals include

• rapid innovation and deployment of capabilities for product or process characterization and monitoring,
• technologies to enable isotope production with novel separations capabilities or other innovative recovery from enrichment process, or
• technique improvements for fundamental actinide diagnostics and characterization.

All ideas that support establishing and advancing capabilities in actinide research and manufacturing systems needed to enable Laboratory mission agility and scientific advancement will be considered.

Technical contact: Franz Freibert

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Theoretical

Determination of neutron star radii enhances understanding of densest matter in the cosmos

Los Alamos National Laboratory contributed to a significant collaborative study resulting in the radius determination of a 1.4-M_⊙ neutron star. The research approach was novel—combining the first observation of a binary neutron-star merger with nuclear theory that provides theoretical uncertainty estimates. Previous studies lacked proper accounts of such density-dependent theoretical uncertainties.

This new method enabled the most stringent constraints to date on a neutron-star radius and led to the finding that neutron stars are unlikely to be disrupted in neutron-star black-hole mergers.

“Neutron-star mergers enable us to unravel the nature of the densest matter in the universe,” said Ingo Tews, staff scientist in LANL’s Theoretical Division.

Neutron stars are multi-messengers

Neutron stars are remnants of supernovae with extreme properties. For example, they contain the mass of our Sun in a sphere that’s only a few tens of kilometers in diameter. Hence, the core of a neutron star is made up of extremely dense nuclear matter and can, therefore, teach us a great deal about quantum chromodynamics (the fundamental theory of strong interactions). However, little can be interpreted from neutron-star observations without a proper radius measurement.

When two neutron stars collide in a so-called neutron-star merger, they give off multi-messenger signals, such as gravitational waves, electromagnetic radiation, and neutrinos. The collaborators combined state-of-the-art low-energy nuclear theory constrained by experimental data with multi-messenger observations from a physically close binary neutron-star merger, called GW170817, to determine the neutron-star radius. They found the radius of a 1.4-M_⊙ neutron star to be 11.0± km.

 

Chiral effective field theory describes equation of state

For this new approach, the researchers turned to chiral effective field theory. At low density, neutron-star matter can be described in terms of nucleons, mostly neutrons and only 5–10% protons. Chiral effective field theory describes the interactions among these nucleons in terms of an expansion in powers of momenta.

This expansion enables a systematic improvement of nuclear interactions as well as reliable theoretical uncertainty estimates from neglected contributions. Subsequently, quantum Monte Carlo techniques (which were developed at Los Alamos National Laboratory) were used to obtain the equation of state with uncertainty estimates, which was then extended to higher densities in a model-agnostic way. Lastly, the multi-messenger observations were used to constrain the equation of state and determine the radius of the neutron stars.

“Our research allowed us to considerably constrain the properties of dense matter in the core of neutron stars using neutron-star merger observations,” Tews said. “The analysis of these remarkable astrophysical events requires an interdisciplinary approach with participation from observers, nuclear physicists, and gravitational-wave and numerical astrophysicists. Los Alamos National Laboratory is an ideal place for this kind of research.”

Funding and mission

This work was supported by the U.S. National Science Foundation, the NASA Space Telescope Science Institute, the U.S. Department of Energy, Office of Science, Office of Nuclear Physics, the Los Alamos LDRD program, and the NUCLEI SciDAC program. Computational resources were provided by Los Alamos Open Supercomputing via the Institutional Computing (IC) program, the National Energy Research Scientific Computing Center (NERSC), the Julich Supercomputing Center, the ATLAS Cluster at the Albert Einstein Institute in Hannover, and Syracuse University. The work supports the Laboratory’s Global Security mission area and the Nuclear and Particle Futures capability pillar.

Reference: Collin D. Capano (Max-Planck-Institut fur Gravitationsphysik), Ingo Tews, Stephanie M. Brown (Leibniz Universitat Hannover), Ben Margalit (UC Berkeley), Soumi De (UC Santa Barbara), Sumit Kumar, Duncan A. Brown (Syracuse University), Badri Krishnan, Sanjay Reddy (U. of Washington; Michigan State University). “Stringent constraints on neutron-star radii from multimessenger observations and nuclear theory.” Nature Astronomy. Accepted January 2020. arXiv:1908.10352 [astro-ph.HE]

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