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Waters, Katrina

Publications and source records attributed to Waters, Katrina.

Proteome-wide characterization of PTMs reveals host cell responses to viral infection and identifies putative antiviral drug targets

Post-translational modifications (PTMs) are biochemical modifications that can significantly alter protein structure, function, stability, localization, and interactions with other molecules, thereby activating or inactivating intracellular processes. A growing body of research has begun to highlight the role of PTMs, including phosphorylation, ubiquitination, acetylation, and redox modifications, during virus-host interactions. Collectively, these PTMs regulate key steps in mounting the host immune response and control critical host pathways required for productive viral replication. This has led to the conception of antiviral therapeutics that focus on controlling host protein PTMs, potentially offering pathogen-agnostic treatment options and revolutionizing our capacity to prevent virus transmission. On the other hand, viruses can hijack the host cellular PTM machinery to modify viral proteins in promoting viral replication and evading immune surveillance. PTM regulation during virus-host interactions is complex and poorly mapped, and the development of effective PTM-targeted antiviral drugs will require a more comprehensive understanding of the cellular pathways essential for virus replication. In this review, we discuss the roles of PTMs in virus infection and how technological advances in mass spectrometry-based proteomics can capture systems-level PTM changes during viral infection. Additionally, we explore how such knowledge is leveraged to identify PTM-targeted candidates for developing antiviral drugs. Looking ahead, studies focusing on the discovery and functional elucidation of PTMs, either on the host or viral proteins, will not only deepen our understanding of molecular pathology but also pave the way for developing better drugs to fight emerging viruses.

Immunology↗

PNNL-CompBio/bmdrc

Python library for the calculation of benchmark dose response curves

Degnan, David↗

U.S. Department of Energy: National Virtual Biotechnology Laboratory (Technical Report)

With funding from the CARES Act, the U.S Department of Energy (DOE) established the National Virtual Biotechnology Laboratory (NVBL) in March 2020 to address key challenges associated with the COVID-19 crisis. The NVBL brought together the broad scientific and technical expertise and resources of DOE’s 17 national laboratories to help tackle medical supply shortages, discover potential drugs to fight the virus, develop and validate COVID-19 testing methods, model disease spread and impact across the nation, and understand virus transport in buildings and the environment. National laboratory resources leveraged for this effort include a suite of world-leading user facilities broadly available to the research community, such as light and neutron sources, nanoscale science research centers, sequencing and biocharacterization facilities, and high-performance computing facilities. As part of the NVBL framework, DOE rapidly assembled five project teams to (1) identify new targets for medical therapeutics; (2) develop innovations in testing capabilities; (3) provide epidemiological and logistical support; (4) understand viral fate and transport in the environment; and (5) address supply chain bottlenecks by harnessing extensive additive manufacturing capabilities. Each research team was charged with defining high-impact projects that could be completed in a 6-month sprint while coordinating their developments with academia, other government agencies, and the private sector. Within months, NVBL teams used DOE’s high-performance computers and light and neutron sources to identify promising candidates for antibodies and antivirals that universities and drug companies are now evaluating. NVBL researchers also developed new diagnostic targets and sample collection approaches, and supported efforts by the U.S. Food and Drug Administration, Centers for Disease Control and Prevention, and U.S. Department of Defense to establish national guidelines used in administering millions of tests. Researchers used artificial intelligence and high-performance computing to produce near-real-time data analysis to forecast disease transmission, stress on public health infrastructure, and economic impact, which supported decision-makers at the local, state, and national levels. To minimize virus uptake and protect human health, NVBL teams studied how to control indoor virus movement. Researchers also produced innovations in materials and advanced manufacturing that mitigated shortages in test kits and personal protective equipment, creating nearly 1,000 new jobs. Through its NVBL framework, DOE has contributed significantly to the nation’s COVID response, demonstrating in only a few months the critical impact of its national laboratories. NVBL’s accomplishments demonstrate not only the powerful resource represented by DOE’s national laboratories working together to meet national needs, but also the effectiveness of the integrated NVBL framework for rapidly responding to emergencies with research and development solutions. Going forward, the NVBL is poised to apply the unique capabilities and expertise of the national laboratory complex to future national and international emergencies, both natural and engineered. Through this framework, DOE will continue to be an integral component of agency-wide efforts to prepare for and respond to biorisks and other crises. This technical report describes the goals, progress, and results of NVBL’s five project teams—Molecular Design for COVID-19 Therapeutics, COVID-19 Testing, Epidemiological Modeling, Viral Fate and Transport, and Materials and Manufacturing of Critical Supplies—and lists each team’s publications and research output.

42 ENGINEERING↗

National Virtual Biotechnology Laboratory: Report on Rapid R&D Solutions to the COVID-19 Crisis

With funding from the CARES Act, the U.S Department of Energy (DOE) established the National Virtual Biotechnology Laboratory (NVBL) in March 2020 to address key challenges associated with the COVID-19 crisis. NVBL brought together the broad scientific and technical expertise and resources of DOE’s 17 national laboratories to help tackle medical supply short ages, discover potential drugs to fight the virus, develop and validate COVID-19 testing methods, model disease spread and impact across the nation, and understand virus transport in buildings and the environment. National laboratory resources leveraged for this effort include a suite of world-leading user facilities broadly available to the research community, such as light and neutron sources, nanoscale science research centers, sequencing and biocharacterization facilities, and high-performance computing facilities. Within months, NVBL teams produced innovations in materials and advanced manufacturing that mitigated shortages in test kits and personal protective equipment (PPE), creating nearly 1,000 new jobs. They used DOE’s high-performance computers and light and neutron sources to identify promising candidates for antibodies and antivirals that universities and drug companies are now evaluating. NVBL researchers also developed new diagnostic targets and sample collection approaches, and supported U.S. Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), and U.S. Department of Defense (DoD) efforts to establish national guidelines used in administering millions of tests. Researchers used artificial intelligence and high-performance computing to produce near-real-time data analysis to forecast disease transmission, stress on public health infrastructure, and economic impact, which supported decision-makers at the local, state, and national levels. NVBL teams also studied how to control indoor virus movement to minimize uptake and protect human health. NVBL’s accomplishments demonstrate not only the powerful resource represented by DOE’s national laboratories working together to meet national needs, but also the effectiveness of the integrated NVBL framework for rapidly responding to emergencies with research and development (R&D) solutions. As the fight against COVID continues, sustained efforts are needed to confront this pandemic as well as future threats. Examples include: 1) Establishing “supply chains on demand” to meet emergency production needs by leveraging the materials and manufacturing expertise of DOE national laboratories and developing advances in electronics, sensing, robotics, and automation capabilities; 2) Improving the speed and robustness of drug discovery by integrating experimental platforms with DOE’s computational and experimental user facilities, which provide unique resources to support the discovery of high-potential therapeutic agents; 3) Protecting public, environmental, and animal health by developing new testing protocols and instrumentation adaptable to diverse sample types (both physiological and environmental) to quickly detect a wide range of pathogens and monitor other biorisks; 4) Supporting near-real-time data needs of decision-makers at the local, regional, state, and national levels by advancing data curation, analysis, and modeling using artificial intelligence and new data science tools for managing and evaluating large diverse datasets; 5) Harnessing DOE’s expertise in environmental modeling to design rooms and air handling for offices, classrooms, restaurants, and other structures to minimize biorisk transmissions. Going forward, NVBL is poised to apply the unique capabilities and expertise of the national laboratory complex to future national and international emergencies, both natural and engineered. Through this framework, the Office of Science will continue to be an integral component of agency wide efforts to prepare for and respond to biorisks and other crises.

42 ENGINEERING↗

Viral Fate and Transport for COVID-19

The NVBL Viral Fate and Transport Team includes researchers from eleven DOE national laboratories and is utilizing unique experimental facilities combined with physics-based and data-driven modeling and simulation to study the transmission, transport, and fate of SARSCoV-2. The team was focused on understanding and ultimately predicting SARS-CoV-2 viability in varied environments with the goal of rapidly informing strategies that guide the nation’s resumption of normal activities. The primary goals of this project include prioritizing administrative and engineering controls that reduce the risk of SARS-CoV-2 transmission within an enclosed environment; identifying the chemical and physical properties that influence binding of SARS-CoV-2 to common surfaces; and understanding the contribution of environmental reservoirs and conditions on transmission and resurgence of SARS-CoV-2.

54 ENVIRONMENTAL SCIENCES↗

NVBL (National Virtual Biotechnology Laboratory) Viral Fate and Transport for COVID-19

This virtual symposium was held to highlight the impact the U.S. Department of Energy’s (DOE) National Virtual Biotechnology Laboratory (NVBL) has had utilizing the unique capabilities of the DOE to tackle the science and technology challenges associated with COVID-19, and to discuss areas in which the NVBL can have impact in the future. With perspectives from Chris Fall, Director, Office of Science, DOE, and William A. Bookless, Principal Deputy Administrator of the National Nuclear Security Administration, the event featured Presentations from lead investigators reporting progress in: Epidemiological modeling, Therapeutics, Testing, Understanding transport of the virus, and Solving issues around supply chain challenges. In addition, keynote speakers from outside the NVBL discussed the upcoming science and technology needs in computing, testing and surveillance, and vaccines. The event was aimed at the S&T community, media, and general public.

Waters, Katrina↗

Bioinformatics Resource Manager

The Bioinformatics Resource Manager (BRM) is a web-based tool developed to facilitate identifier conversion and data integration for Homo sapiens (human), Mus musculus (mouse), Rattus norvegicus (rat), Danio rerio (zebrafish), and Macaca mulatta (macaque), as well as perform orthologous conversions among the supported species. In addition to providing a robust means of identifier conversion, BRM also incorporates a suite of miRNA-target databases upon which to query target genes or to perform reverse target lookups using gene identifiers.

Brown, Joseph↗