Showing papers in "Science in 2022"

Copper induces cell death by targeting lipoylated TCA cycle proteins

Abstract: Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms. Description Copper induces cell death Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al. investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK Lipoylation determines sensitivity to copper-induced cell death.

Early detection of cancer

Abstract: Survival improves when cancer is detected early. However, ~50% of cancers are at an advanced stage when diagnosed. Early detection of cancer or precancerous change allows early intervention to try to slow or prevent cancer development and lethality. To achieve early detection of all cancers, numerous challenges must be overcome. It is vital to better understand who is at greatest risk of developing cancer. We also need to elucidate the biology and trajectory of precancer and early cancer to identify consequential disease that requires intervention. Insights must be translated into sensitive and specific early detection technologies and be appropriately evaluated to support practical clinical implementation. Interdisciplinary collaboration is key; advances in technology and biological understanding highlight that it is time to accelerate early detection research and transform cancer survival. Description Detecting cancer early Many types of cancer are detected at an advanced stage, when treatment options are limited and prognosis is poor. Being able to detect cancers early can substantially improve survival, but this approach comes with challenges, including the possibility of overdiagnosis and overtreatment, which can harm people who would not have developed overt malignancy. In a Review, Crosby et al. discuss the importance of cancer early detection and the main challenges that need to be overcome to better understand the early events in tumorigenesis that are detectable in screening tests. The results of these tests can then be reliably interpreted to determine whether an individual requires treatment. —GKA A review discusses approaches to enable early detection of cancer and allow earlier intervention and increase survival. BACKGROUND When cancer is detected at the earliest stages, treatment is more effective and survival drastically improves. Yet ~50% of cancers are still only detected at an advanced stage. Improved earlier detection of cancer could substantially increase survival rates. Although recent advances in early detection have saved lives, further innovations and development of early cancer detection approaches are needed. The field is evolving rapidly, owing to advances in biological understanding and an increasing pace of technological progress. ADVANCES We highlight five challenges facing the field, current work in those areas, and where more research is needed to make early detection a reality. The first challenge is to build a greater understanding of the biology and behavior of early disease. This will help identify ways to distinguish between consequential, aggressive lesions and inconsequential lesions that will not cause harm. Such insight will be crucial to realizing the potential for early detection to inform treatment decisions and improve survival, while minimizing the risk of overtreatment. Alongside studies in human samples, better models of disease are enabling identification of early signals of tumorigenesis and clarifying the contributions of the immune system and microenvironment to tumor development. The second challenge is determining the risk of developing cancer. How can we use germline genomic susceptibility, family history, exposures, demographic, and behavioral data to build nuanced risk models to identify who should be tested for cancer and how test results should be interpreted and followed up? Progress is being made to address this challenge through improved understanding of the genomics of cancer risk, integration of that insight with other risk factors, and the development of large-scale population cohorts where risk models can be developed and validated. The third challenge is finding and validating biomarkers of early cancer. There is considerable difficulty in finding accurate signals of early cancer (which usually exist in very small amounts) amid the noise of normal human physiology. Although progress has historically been slow, many promising early detection markers are emerging, including circulating tumor DNA, circulating tumor cells, proteins, exosomes, and cancer metabolites. Advances in data analysis methodologies (such as machine learning) and integration across marker types in multimodal tests are also accelerating progress. The fourth challenge is technological. It involves both the iterative improvement of existing approaches and the development of disruptive detection technologies that can very sensitively and specifically identify early biological changes, whether in tissue structure, biochemistry, or function. Powerful molecular analytical technologies and advanced imaging and histopathological methods are increasing the ability to sensitively find earlier tumors, while the use of synthetic markers may help to amplify their signal. The fifth challenge is how to appropriately evaluate early detection approaches. Translation of biological insights into new diagnostic technologies and execution of clinical trials to validate those advances require substantial time and money. We discuss ways in which that process might be improved. OUTLOOK For early detection to deliver transformative progress in cancer survival, wider skill sets beyond cancer biology are essential, including engineers, chemists, physicists, technology developers, and behavioral and computer scientists. Integrated, interdisciplinary collaboration is key to bringing new ideas to address the challenges of early cancer detection. We believe that early detection of cancer is approaching a tipping point, as biological insight and technological capacity are increasing at an unprecedented rate and as public and private funders of research are increasingly willing to invest. This Review discusses the current state of the field and suggests constructive ways forward that build on current progress to deliver effective earlier detection of cancer and appropriate intervention. The early detection of cancer—challenges and ways forward. This figure summarizes challenges that impede the early detection of cancer and the areas of current research that are helping to overcome them.

Soybean photosynthesis and crop yield are improved by accelerating recovery from photoprotection

Abstract: Crop leaves in full sunlight dissipate damaging excess absorbed light energy as heat. This protective dissipation continues after the leaf transitions to shade, reducing crop photosynthesis. A bioengineered acceleration of this adjustment increased photosynthetic efficiency and biomass in tobacco in the field. But could that also translate to increased yield in a food crop? Here we bioengineered the same change into soybean. In replicated field trials, photosynthetic efficiency in fluctuating light was higher and seed yield in five independent transformation events increased by up to 33%. Despite increased seed quantity, seed protein and oil content were unaltered. This validates increasing photosynthetic efficiency as a much needed strategy toward sustainably increasing crop yield in support of future global food security. Description More soybeans by light management Plants protect themselves from too much sun by dissipating excess light energy. Unfortunately, the switch from dissipating light energy to using light energy for photosynthesis is not as nimble as the clouds moving across the sky. De Souza et al. applied a bioengineered solution that speeds up accommodation by nonphotochemical quenching in soybeans, a widely cultivated and essential crop. In field trials, seed yield increased in some cases up to 33%. —PJH Bioengineering to improve regulation of photoprotection increases photosynthetic efficiency and seed yield in soybean.

Low-temperature mineralization of perfluorocarboxylic acids

Abstract: Per- and polyfluoroalkyl substances (PFAS) are persistent, bioaccumulative pollutants found in water resources at concentrations harmful to human health. Whereas current PFAS destruction strategies use nonselective destruction mechanisms, we found that perfluoroalkyl carboxylic acids (PFCAs) could be mineralized through a sodium hydroxide–mediated defluorination pathway. PFCA decarboxylation in polar aprotic solvents produced reactive perfluoroalkyl ion intermediates that degraded to fluoride ions (78 to ~100%) within 24 hours. The carbon-containing intermediates and products were inconsistent with oft-proposed one-carbon-chain shortening mechanisms, and we instead computationally identified pathways consistent with many experiments. Degradation was also observed for branched perfluoroalkyl ether carboxylic acids and might be extended to degrade other PFAS classes as methods to activate their polar headgroups are identified. Description Forever chemicals’ Achilles’ heel Per- and polyfluoroalkyl substances (PFAS) have been referred to as “forever chemicals” because of their resistance to most biological and chemical degradation mechanisms. Most current methods use very harsh conditions to decompose these compounds. Trang et al. found that there is a potential weak spot in carboxylic acid–containing PFAS: Decarboxylation in polar, non-protic solvents yields a carbanion that rapidly decomposes (see the Perspective by Joudan and Lundgren). The authors used computational work and experiments to show that this process involves fluoride elimination, hydroxide addition, and carbon–carbon bond scission. The initial decarboxylation step is rate limiting, and subsequent defluorination and chain shortening steps occur through a series of low barrier steps. The procedure can accommodate perfluoroether carboxylic acids, although sulfonic acids are not currently compatible. —MAF Mechanistic insights into a decarboxylation–defluorination pathway inform methods for perfluorocarboxylic acid mineralization.

Monkeypox outbreak questions intensify as cases soar

Abstract: Description Rapid emergence of hundreds of cases around the world alarms public health officials and scientists Rapid emergence of hundreds of cases around the world alarms public health officials and scientists

Dynamics of particle network in composite battery cathodes

Abstract: Improving composite battery electrodes requires a delicate control of active materials and electrode formulation. The electrochemically active particles fulfill their role as energy exchange reservoirs through interacting with the surrounding conductive network. We formulate a network evolution model to interpret the regulation and equilibration between electrochemical activity and mechanical damage of these particles. Through statistical analysis of thousands of particles using x-ray phase contrast holotomography in a LiNi0.8Mn0.1Co0.1O2-based cathode, we found that the local network heterogeneity results in asynchronous activities in the early cycles, and subsequently the particle assemblies move toward a synchronous behavior. Our study pinpoints the chemomechanical behavior of individual particles and enables better designs of the conductive network to optimize the utility of all the particles during operation. Description Observations of cathode evolution The loss of capacity in a rechargeable battery can be due to changes in the electrode structure that occur with cycling. Li et al. used hard x-ray holotomography to visualize the structure of a nickel-rich LiNi0.8Mn0.1Co0.1O2 composite cathode (see the Perspective by Xiao). They were able to track the behavior of thousands of individual particles with time and thus determine the relationship between structure and performance as well as the deterioration of the cathode at a size scale that is not generally accessible. They found that damage during cycling is driven not only by each particle but also by its surrounding neighbors, although the contributions shift over time. This work suggests ways to better design electrodes to maximize their performance. —MSL Active particles in composite electrodes initially show asynchronous activity that evolves toward synchronous behavior.

Avoiding ocean mass extinction from climate warming

Abstract: Global warming threatens marine biota with losses of unknown severity. Here, we quantify global and local extinction risks in the ocean across a range of climate futures on the basis of the ecophysiological limits of diverse animal species and calibration against the fossil record. With accelerating greenhouse gas emissions, species losses from warming and oxygen depletion alone become comparable to current direct human impacts within a century and culminate in a mass extinction rivaling those in Earth’s past. Polar species are at highest risk of extinction, but local biological richness declines more in the tropics. Reversing greenhouse gas emissions trends would diminish extinction risks by more than 70%, preserving marine biodiversity accumulated over the past ~50 million years of evolutionary history. Description Rising temperatures, rising risks Climate change brings with it the increasing risk of extinction across species and systems. Marine species face particular risks related to water warming and oxygen depletion. Penn and Deutsch looked at extinction risk for marine species across climate warming and as related to ecophysiological limits (see the Perspective by Pinsky and Fredston). They found that under business-as-usual global temperature increases, marine systems are likely to experience mass extinctions on par with past great extinctions based on ecophysiological limits alone. Drastically reducing global emissions, however, offers substantial protection, which emphasizes a need for rapid action to prevent possibly catastrophic marine extinctions. —SNV Climate change threatens marine biodiversity with a mass extinction unless greenhouse gases are rapidly stabilized.

Meeting of Minds.

Abstract: Rejuvenation will be an important theme at the 102nd TRB Annual Meeting in January 2023. Global industry professionals are set to share expertise and provide insight that will help equip all areas of the transportation industry for the future

Monkeypox vaccination plans take shape amid questions

Abstract: Description Favored shot is a seemingly safer smallpox vaccine, but researchers debate how best to use it Favored shot is a seemingly safer smallpox vaccine, but researchers debate how best to use it

Diversity and ecological footprint of Global Ocean RNA viruses

Abstract: DNA viruses are increasingly recognized as influencing marine microbes and microbe-mediated biogeochemical cycling. However, little is known about global marine RNA virus diversity, ecology, and ecosystem roles. In this study, we uncover patterns and predictors of marine RNA virus community- and “species”-level diversity and contextualize their ecological impacts from pole to pole. Our analyses revealed four ecological zones, latitudinal and depth diversity patterns, and environmental correlates for RNA viruses. Our findings only partially parallel those of cosampled plankton and show unexpectedly high polar ecological interactions. The influence of RNA viruses on ecosystems appears to be large, as predicted hosts are ecologically important. Moreover, the occurrence of auxiliary metabolic genes indicates that RNA viruses cause reprogramming of diverse host metabolisms, including photosynthesis and carbon cycling, and that RNA virus abundances predict ocean carbon export. Description Patterns and process in RNA viruses Viruses are suspected to be lynchpins in ecosystem function, but so far we can only guess at their significance. DNA viruses are increasingly being recognized as significant components of biogeochemical cycling in the oceans. Dominguez-Huerta et al. explored global patterns of marine RNA virus occurrence by extracting virus sequences from Tara Ocean samples. Host prediction analysis identified predominantly protist and fungal hosts plus a few invertebrates. Like double-stranded DNA viruses and their hosts, RNA viruses showed marked depth limitation but little latitudinal change. Auxiliary metabolic genes in the RNA virome indicated that several eukaryote plankton processes are affected by viruses. A group of 11 RNA viruses that significantly influence ocean carbon flux were identified. —CA Community- and “species”-level analyses elucidate ecological impacts and roles of marine RNA viruses.

Vernier template synthesis of molecular knots

Abstract: Molecular knots are often prepared using metal helicates to cross the strands. We found that coordinatively mismatching oligodentate ligands and metal ions provides a more effective way to synthesize larger knots using Vernier templating. Strands composed of different numbers of tridentate 2,6-pyridinedicarboxamide groups fold around nine-coordinate lanthanide (III) ions to generate strand-entangled complexes with the lowest common multiple of coordination sites for the ligand strands and metal ions. Ring-closing olefin metathesis then completes the knots. A 3:2 (ditopic strand:metal) Vernier assembly produces +31#+31 and −31#−31 granny knots. Vernier complexes of 3:4 (tetratopic strand:metal) stoichiometry selectively form a 378-atom-long trefoil-of-trefoils triskelion knot with 12 alternating strand crossings or, by using opposing stereochemistry at the terminus of the strand, an inverted-core triskelion knot with six alternating and six nonalternating strand crossings. Description Opportune mismatches The typical approach to making molecular knots is to use metal ions to orient ligand strands in mutually overlapping arrangements. Ashbridge et al. added a Vernier templating technique to expand the size and complexity of accessible knots. Specifically, they introduced a mismatch between the numbers of coordination sites on the ligands and on the metal ions, resulting in an assembly comprising the lowest common multiple of sites. A 3:4 stoichiometry produced a 378-atom trefoil-of-trefoils after ring closure by olefin metathesis. —JSY A mismatch between numbers of coordination sites on ligand strands and on metal nodes expands the size of accessible knots.

Will viral interference hold off the tripledemic?

Abstract: Description As multiple respiratory viruses surge, some researchers predict they will block one another As multiple respiratory viruses surge, some researchers predict they will block one another

Nanocrystals with metastable high-pressure phases under ambient conditions

Abstract: The ambient metastability of the rock-salt phase in well-defined model systems comprising nanospheres or nanorods of cadmium selenide, cadmium sulfide, or both was investigated as a function of composition, initial crystal phase, particle structure, shape, surface functionalization, and ordering level of their assemblies. Our experiments show that these nanocrystal systems exhibit ligand-tailorable reversibility in the rock salt–to–zinc blende solid-phase transformation. Interparticle sintering was used to engineer kinetic barriers in the phase transformation to produce ambient-pressure metastable rock-salt structures in a controllable manner. Interconnected nanocrystal networks were identified as an essential structure that hosted metastable high-energy phases at ambient conditions. These findings suggest general rules for transformation-barrier engineering that are useful in the rational design of next-generation materials. Description Ligand-driven metastability A high-pressure phase of a solid can persist at ambient pressure if there are kinetic barriers to its relaxation. Xiao et al. performed detailed mechanistic studies on the reversibility of four- to six-coordinate pressure-driven solid-phase transitions in well-controlled model systems of nanospheres or nanorods of cadmium selenide, cadmium sulfide, or both (see the Perspective by Mao and Lin). The choice of surface ligands could control the reversibility of the transformations. Interparticle sintering helped to eliminate crystal defects and relaxed lattice distortions from the high-pressure rock-salt structures to maintain their ambient-pressure metastability. —PDS Interparticle sintering can stabilize high-pressure phases of cadmium selenide and cadmium sulfide nanocrystal networks at ambient conditions.

Doubly stereoconvergent crystallization enabled by asymmetric catalysis

Abstract: Synthetic methods that enable simultaneous control over multiple stereogenic centers are desirable for the efficient preparation of pharmaceutical compounds. Herein, we report the discovery and development of a catalyst-mediated asymmetric Michael addition/crystallization–induced diastereomer transformation of broad scope. The sequence controls three stereogenic centers, two of which are stereochemically labile. The configurational instability of 1,3-dicarbonyls and nitroalkanes, typically considered a liability in stereoselective synthesis, is productively leveraged by merging enantioselective Brønsted base organocatalysis and thermodynamic stereocontrol using a single convergent crystallization. The synthesis of useful γ-nitro β-keto amides containing three contiguous stereogenic centers is thus achieved from Michael acceptors containing two prochiral centers. Description Catalysis paired with crystallization Asymmetric catalysis often distinguishes mirror-image configurations at a single carbon center. However, many complex molecules have three or more chiral centers, and selecting just one of the ballooning number of diastereomers in such cases can be daunting. In this context, de Jesús Cruz et al. report that product crystallization during the reaction can supplement the catalyst’s intrinsic selectivity. Specifically, the authors used a chiral base to set one stereocenter in a Michael addition of nitroalkanes to ketoamides while dynamically scrambling the configurations on the adjacent carbons. Crystallization then selects a single diastereomer from this interconverting mixture. —JSY Chiral base catalysis paired with product crystallization can set three adjacent stereocenters in a Michael addition.

Intensification of subhourly heavy rainfall

Abstract: Short-duration rainfall extremes can cause flash flooding with associated impacts. Previous studies of climate impacts on extreme precipitation have focused mainly on daily rain totals. Subdaily extremes are often generated in small areas that can be missed by gauge networks or satellites and are not resolved by climate models. Here, we show a robust positive trend of at least 20% per decade in subhourly extreme rainfall near Sydney, Australia, over 20 years, despite no evidence of trends at hourly or daily scales. This trend is seen consistently in storms tracked using multiple independent ground radars, is consistent with rain-gauge data, and does not appear to be associated with known natural variations. This finding suggests that subhourly rainfall extremes may be increasing substantially faster than those on more widely reported time scales. Description A hard rain is falling Short-duration, extreme rainfall can cause dangerous flash flooding, threatening life, infrastructure and the landscape. Studies of this type of event have focused mainly on daily rain totals, not considering how precipitation might vary on shorter time scales. Ayat et al. analyzed subhourly rainfall extremes near Sydney, Australia, over 20 years and found that they are increasing much faster than those over longer periods. Better understanding of such extremes is vital for effective climate adaptation and to reduce the vulnerability of populated regions. —HJS Subhourly rainfall extremes are intensifying faster than those on longer time scales.

Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine

Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through the leucine-binding Sestrin proteins, but the physiological functions and distribution of Sestrin-mediated leucine sensing in mammals are unknown. We find that mice lacking Sestrin1 and Sestrin2 cannot inhibit mTORC1 upon dietary leucine deprivation and suffer a rapid loss of white adipose tissue (WAT) and muscle. The WAT loss is driven by aberrant mTORC1 activity and fibroblast growth factor 21 (FGF21) production in the liver. Sestrin expression in the liver lobule is zonated, accounting for zone-specific regulation of mTORC1 activity and FGF21 induction by leucine. These results establish the mammalian Sestrins as physiological leucine sensors and reveal a spatial organization to nutrient sensing by the mTORC1 pathway. Description Leucine sensing in the zone Leucine is an essential amino acid that plays an important role in a variety of metabolic processes, including both physiological ones such as insulin secretion and pathological ones involved in the metabolic syndrome. mTORC1 is a key protein that is also involved in many aspects of metabolism and senses leucine through proteins called sestrins. Some aspects of this signaling pathway were previously observed in cultured cells, but now Cangelosi et al. have identified what happens in vivo in a mammal. The authors clarified the signaling steps involved in mTORC1 sensing of leucine through sestrins in mice and determined that the regulation of this pathway varies between different zones within the liver based on proximity to blood vessels. —YN Sestrins are leucine sensors in mice that control hepatic responses to dietary leucine availability.

Business decisions.

Abstract: F or academics, the journey from a discovery to a product can be arduous. But as a culture of entrepreneurship has spread to universities across the country and around the world, aid stations have popped up to ease the way. They come in various forms, including campus competitions to solicit commercially viable ideas, universities establishing their own venture capital funds and “incubators” to nurture startup companies, and programs such as the Innovation Corps (ICorps) at the National Science Foundation. “We all know that entrepreneurship is the big buzzword today on campus,” says Laura Ray, an engineer at Dartmouth College, who has founded two firms based on her work in acoustics and signal detection and runs a graduate fellowship program in innovation. Ray’s own entrepreneurial learning curve has been steep. Her first company, begun in 2005, was the result of a knock on the door from a university tech transfer official who asked if she had anything that could be taken to market. “We thought he was crazy,” Ray recalls— but she was willing to take a shot. Eight years later, a second company grew out of her participation in I-Corps’ 10-week boot camp for would-be academic entrepreneurs. “I-Corps opened my eyes,” Ray says. “It taught me that you need to know the customer, and your value proposition—that is, how you plan to make money.” Despite those commercial ventures, Ray has remained an academic. And although some scientists leave campus to follow their commercial dreams, most do not. They like research and teaching, for one thing, and may not think they have what it takes to run a

Molten iron in Earth-like exoplanet cores

Abstract: Description Iron crystallization in super-Earth interiors plays a key role in their habitability Earth, the only known habitable planet in the Universe, has a magnetic field that shields organic life-forms from harmful radiation coming from the Sun and beyond. This magnetic field is generated by the churning of molten iron in its outer core. The habitability of exoplanets orbiting other stars could be gleaned through better understanding of their iron cores and magnetic fields (1). However, extreme pressure and temperature conditions inside exoplanets that are much heavier than Earth may mean that their cores behave differently. On page 202 of this issue, Kraus et al. (2) used a powerful laser to generate conditions similar to those inside the cores of such “super-Earths” and reveal that even under extreme conditions, molten iron can crystallize similarly to that found at the base of Earth’s outer core.

Streamlining ethics review for international health research

Abstract: Single-site review means protection and efficiency International biomedical research, in which projects span borders and engage participants from multiple countries, has increased substantially during the last several decades. Despite the proven value of large, geographically, and ethnically diverse studies, further advancements are being impeded by the burden of submitting separate, and often numerous, applications for research ethics approval in compliance with country-specific laws or varied policy frameworks. To address this, we see promise in applying the international concept of “adequacy,” contained in the European Union (EU) General Data Protection Regulation (GDPR) (1), to ethics review of international health research. We advocate for countries to publish their prior determinations about the adequacy of ethics review requirements in other countries to enable review by one institutional review board (IRB) or comparable body (“single-site” review) in the researcher’s country, streamlining ethics review while safeguarding the welfare of local research participants.

Human origins.

Abstract: New discoveries combine to indicate that all the major steps in human evolution took place in Africa. Skeletal analysis of oldest human forbears around 3 million years ago reveal many anatomical similarities to African Great Apes. These and biochemical resemblances indicate a common ancestry for humans and apes, perhaps only a few million years earlier. Enlarged knowledge through recent recovery of skeletons of several successive stages in the line leading to modern peoples shows that many attributes or skills by which we define humanity arose much more recently in time than heretofore believed.

In memoriam.

Abstract:

The digital citizen

Abstract: Description Two new books advocate for technological agency Two new books advocate for technological agency

Mysterious strains show power—and limitations—of wastewater monitoring

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Stepping out of my comfort zone

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Massive climate and health bill also benefits U.S. energy labs

Abstract: Major physics projects and national lab infrastructure will get $1.5 billion over 5 years Major physics projects and national lab infrastructure will get $1.5 billion over 5 years