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At least 973 records · Page 54
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Identifying Fungal Secondary Metabolites and Their Role in Plant Pathogenesis

Pathogenic fungi are the main infectious agents of plants. Secondary metabolites produced by these fungi, also recognized as natural products, are key mediators of plant-fungal interactions. Knowledge on the biosynthesis of these metabolites, the accessibility to fungal genome sequences, and the development of gene disruption techniques open up opportunities to identify many more of these metabolites both in vitro and in planta. This methodology chapter gives a detailed systematic approach aiming to discover new natural products from phytopathogenic fungi and characterize their role in triggering plant cell death and plant disease. This approach takes advantage of the global regulation of fungal secondary metabolite production by regulatory proteins reported in various fungal species.

Tannous, Joanna↗
DOE OSTI2022

Eucalyptus grandis $\mathrm{AUX/INDOLE}$-3-$\mathrm{ACETIC}$ $\mathrm{ACID}$ 13 (EgrIAA13) is a novel transcriptional regulator of xylogenesis

Auxin is a crucial phytohormone regulating multiple aspects of plant growth and differentiation, including regulation of vascular cambium activity, xylogenesis and its responsiveness towards gravitropic stress. Although the regulation of these biological processes greatly depends on auxin and regulators of the auxin signalling pathway, many of their specific functions remain unclear. Therefore, the present study aims to functionally characterise Eucalyptus grandis AUX/INDOLE-3-ACETIC ACID 13 (EgrIAA13), a member of the auxin signalling pathway. In Eucalyptus and Populus, EgrIAA13 and its orthologs are preferentially expressed in the xylogenic tissues and downregulated in tension wood. Therefore, to further investigate EgrIAA13 and its function during xylogenesis, we conducted subcellular localisation and Induced Somatic Sector Analysis experiments using overexpression and RNAi knockdown constructs of EgrIAA13 to create transgenic tissue sectors on growing stems of Eucalyptus and Populus. Since Aux/IAAs interact with Auxin Responsive Factors (ARFs), in silico predictions of IAA13-ARF interactions were explored and experimentally validated via yeast-2-hybrid experiments. Our results demonstrate that EgrIAA13 localises to the nucleus and that downregulation of EgrIAA13 impedes Eucalyptus xylem fibre and vessel development. We also observed that EgrIAA13 interacts with Eucalyptus ARF2, ARF5, ARF6 and ARF19A. Based on these results, we conclude that EgrIAA13 is a regulator of Eucalyptus xylogenesis and postulate that the observed phenotypes are likely to result from alterations in the auxin-responsive transcriptome via IAA13-ARF modules such as EgrIAA13-EgrARF5. Our results provide the first insights into the regulatory role of EgrIAA13 during xylogenesis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

The Role of the U.S. Electric Distribution System in Serving Data Center and Other Large Loads

The rapid expansion of data centers in the United States is reshaping how the electric distribution system must plan for and accommodate large load interconnections. This report evaluates the role of the distribution grid in serving these loads, from small edge facilities to hyperscale campuses. Using national datasets, utility filings, and industry studies, we assess demand growth, reliability requirements, interconnection thresholds, and infrastructure needs at substations and feeders. The analysis highlights the mismatch between fast data center development timelines and slower utility planning and construction cycles, as well as strategies such as phased energization, on-site generation, hosting capacity maps, and structured interconnection frameworks. While focused on data centers, the insights also apply to other high-density loads such as advanced manufacturing, hydrogen production, and electrified transportation. The report concludes with approaches to align planning processes, transparency tools, and regulatory frameworks so utilities can manage new large loads in ways that support a reliable and resilient grid.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗
DOE OSTI2021

Emerging Energy Market Analysis Initiative, Methodological Framework

Planning and operations of the electric power sector are undergoing radical changes. Climate change mitigation efforts have forced rapid changes to the technology mix. Technologies like wind and solar have experienced rapid growth, while investment in fossil sources has peaked or is declining. These foundational changes are forcing changes to energy systems. Demand-side adoption of electrified technologies, including electric vehicles, is changing load profiles and opening up new avenues for consumer participation in the power systems. The implications of an evolving power system pertain to more than environmental and technical dimensions. Changes to the generation mix and its consequent upstream and downstream impacts such as fuel production have significant and highly concentrated consequences on economies and employment. Shifts towards distributed (or decentralized) generating assets offer the potential to reshape economic and employment opportunities associated with the energy sector across space and socioeconomic groups. The Emerging Energy Market Analysis (EMA) initiative aims to identify sustainable, regionally acceptable, and high-value energy solutions that are secure and equitable. Unlike short-term, least-cost choices that can narrowly account for traditional options, EMA’s focus on emerging energy markets recognizes that new or adapted practices and technologies can alter the frontier of solutions and advance a community’s social, economic, and natural pathways. Such change requires a more comprehensive analysis of societal input, resources, capabilities, and infrastructure. These considerations lay the foundation for community decision-making models that are responsive to community values as well as the history and drivers. The result is a community-based decision and engagement model that will be valuable to decisionmakers and developers of advanced and emerging energy solutions, seeking a social license to operate prior to project development.

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗
DOE OSTI2025

High-Burnup BWR LOCA Burst Analysis Using High-Fidelity Multiphysics Simulations

The US nuclear industry is looking to improve on the operating economics of the current fleet of light-water reactors (LWRs). One way of achieving this is by operating fuel to higher burnup. In pressurized water reactors (PWRs), relaxing the current burnup limit will allow for cycle length extensions and power uprates; in boiling water reactors (BWRs) it may allow for improved fuel utilization and reduced feed assemblies, as well as more efficient power uprates and increased capacity factors that will support the Administration’s Executive Order to facilitate 5 GW of power uprates at existing nuclear facilities. However, one of the key limitations to operating fuel to higher burnup is the risk of fuel fragmentation, relocation, and dispersal (FFRD). Recognizing the high interest in extending burnup limits, the US Nuclear Regulatory Commission (NRC) has issued Draft Regulatory Guide DG-1434, which defines an approach that would be acceptable to the NRC for addressing FFRD risk. The approach defined will require better understanding of the phenomena leading to FFRD as well as best-estimate simulation methods to understand FFRD risk in high-burnup cores. The Nuclear Energy Advanced Modeling and Simulation program is supporting the FFRD industry challenge problem through development of state-of-the-art, high-fidelity modeling and simulation LWR analysis capabilities; namely, the BISON fuel performance code and the VERA core simulator software. These tools, along with the US NRC TRACE system analysis code, have been utilized for analysis of FFRD risk in both PWR and BWR cores in recent years. The work documented in this report addresses the lack of high-fidelity research for BWRs and builds on a previous activity where the framework has been applied to Cycles 16 through 18 of Limerick Unit 1, a BWR/4, with introduction of 8 high-burnup lead use assemblies (HBLUAs) that were representative of the 8 HBLUAs loaded into Limerick Unit 2 in 2021. VERA was used in this previous activity to model rod-by-rod depletion in these cycles, and its solution was used to initialize a TRACE simulation of a large-break loss-of-coolant accident (LBLOCA) at the end of Cycle 18. In the work documented in this report, the TRACE model was improved by refining the core mesh and utilizing a new feature that allows for capturing the full 3D VERA power distribution in the model. This allows for a more detailed solution for setting BISON boundary conditions. Furthermore, the solutions from VERA and TRACE were used to set up and perform BISON simulations of about 1,000 rods sampled from the core, including all burnup levels. Utilizing two cladding burst models, it was shown that no fuel rods were predicted to burst during the postulated LBLOCA transient. Additionally, a sensitivity study was performed by artificially increasing linear heat rate during the postulated LBLOCA to identify parameters that correlate with rod burst susceptibility. Burnup, fission gas release, and hoop strain were all found to be positively correlated with rod burst susceptibility. Small-break loss-of-coolant accident (SBLOCA) analyses were also performed; these analyses predicted cladding temperature increases that were bounded by the LBLOCA cladding temperatures for all small break sizes studied for this plant. However, future refinements to the plant response assumptions during the SBLOCA could impact the predicted cladding response. Finally, a benchmark study was performed between CTF and TRACE for LOCA conditions to better qualify CTF for BWR LOCA modeling.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
DOE OSTI2020

A Learning-based Supervisory Control Architecture for Electric Vehicle Charging System Paired with Energy Storages

A Machine Learning-based predictive model is developed for optimal dispatching energy storage system integrated with Electric Vehicle battery charger. The model is effectively trained using transfer learning algorithm and successfully validated via measurement data to achieve high fidelity and accuracy. The study findings provide possibilities for future development of the presented approach to implement computational heavy predictive algorithms with multi-step predictions in emerging modular bidirectional charger topologies to realize vehicle-to-grid (V2G) technology. The online tuning can be explored using the new measurements obtained during the operation, henceforth, enhancing the controller performance for integrating multiple DERs into distribution power networks that shows huge interest for the utilities and regulatory agencies. Multiple operation scenatios have been evaluated and simulation results are discussed to verify intended performance of the proposed control solution.

24 POWER TRANSMISSION AND DISTRIBUTION↗
DOE OSTI2024

National Reactor Innovation Center Annual Report

The National Reactor Innovation Center (NRIC), established in August 2019, is a national United States (U.S.) Department of Energy (DOE) program. NRIC’s mission is to partner with industry and national laboratories to bridge the gap between the concept, demonstration, and commercialization of advanced nuclear technology. NRIC accomplishes this through building or enhancing existing DOE infrastructure to support the testing of components and systems that are key to successfully deploying advanced nuclear technology. NRIC works to inspire stakeholders and the public, empower innovators, and deliver successful outcomes through efficient collaboration and coordination with partners. NRIC’s vision is that by 2028, NRIC will be partnered with industry and accelerating the demonstration and deployment of advanced nuclear technology using DOE national laboratory infrastructure and expertise. NRIC will establish four new experimental facilities and two large reactor test beds for integrated technology demonstrations and experimentation by 2028 and complete two advanced nuclear technology tests by 2030. Achieving this vision will enable urgently needed abundant and affordable clean energy both domestically and internationally. NRIC’s success will inspire our nation and the global community to embrace the promising contribution of innovative nuclear reactor technologies to the clean energy economy and re-establish the U.S. as the global leader in advanced nuclear energy. NRIC is tasked with expediting the development of advanced nuclear energy technologies by bringing together private-sector technology developers and the world-class capabilities of the DOE national laboratory system. Through this program, the U.S. private sector is given access to the physical infrastructure available at DOE national laboratories to test and demonstrate their reactor concepts. NRIC works closely with the Gateway for Accelerated Innovation in Nuclear (GAIN),; which is the DOE-Nuclear Energy (NE) program that grantings access to technical, regulatory, and financial support for commercializing nuclear energy. As observed in Figure 1, NRIC builds upon these new reactor concepts and technology successes to effectively strengthen U.S. nuclear leadership.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2023

Arabidopsis stromal carbonic anhydrases exhibit non–overlapping roles in photosynthetic efficiency and development

Carbonic anhydrases (CAs) are ubiquitous enzymes that accelerate the reversible conversion of CO 2 to HCO 3 – . The Arabidopsis genome encodes members of the α-, β- and γ-CA families, and it has been hypothesized that βCA activity has a role in photosynthesis. In this work, we tested this hypothesis by characterizing the two plastidial βCAs, βCA1 and βCA5, in physiological conditions of growth. We conclusively established that both proteins are localized in the chloroplast stroma and that the loss of βCA5 induced the expression of βCA1, supporting the existence of regulatory mechanisms to control the expression of stromal βCAs. We also established that βCA1 and βCA5 have markedly different enzymatic kinetics and physiological relevance. Specifically, we found that βCA5 had a first-order rate constant ~10-fold lower than βCA1, and that the loss of βCA5 is detrimental to growth and could be rescued by high CO 2 . Furthermore, we established that, while a βCA1 mutation showed near wild-type growth and no significant impact on photosynthetic efficiency, the loss of βCA5 markedly disrupted photosynthetic efficiency and light-harvesting capacity at ambient CO 2 . Therefore, we conclude that in physiological autotrophic growth, the loss of the more highly expressed βCA1 does not compensate for the loss of a less active βCA5, which in turn is involved in growth and photosynthesis at ambient CO 2 levels. These results lend support to the hypothesis that, in Arabidopsis,βCAs have non-overlapping roles in photosynthesis and identify a critical activity of stromal βCA5 and a dispensable role for βCA1.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A Review of Remote Welding and Nondestructive Examination Technologies for the DOE Standard Canister

The U.S. Department of Energy (DOE) manages a wide variety of spent nuclear fuel (SNF) that poses a unique management challenge. To help address this challenge, the DOE Standard Canister (DOESC), designed to remain sealed during handling, storage, transportation, and disposal, was conceptualized as a standardized containment vessel to accommodate DOE-managed SNF. Since 1999, several welding and examination processes have been independently developed for the DOESC’s closure welds. However, neither the DOESC nor these processes have been realized in an operational capacity. This review paper seeks to present and compare previously developed DOESC closure weld, nondestructive examination, and repair processes and technologies. Specific processes developed for the Idaho Spent Fuel Facility, in preparation for the Yucca Mountain geological repository, and the recent Road-Ready Demonstration Project are discussed. Further, specific focus is given to how different operating constraints and the American Society of Mechanical Engineers Boiler and Pressure Vessel Code (BPVC) have driven certain welding and nondestructive examination requirements. Historical DOESC welding and examination strategies are assessed against current regulatory and BPVC requirements. The comparison of welding processes, technologies, and DOESC designs presented in this review paper will inform further construction efforts for other commercial and DOE-managed SNF containments, including the DOESC.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2022

HI-STORM Overpack and MPC-32 Thermal-Hydraulic Model with MOOSE Framework

Nuclear power is a significant source of electricity in the United States, but the average age of nuclear power plants is around 40 years old. The safe management of the spent nuclear fuel (SNF) is a key aspect of the back-end of the nuclear fuel cycle. Spent fuel dry storage systems are becoming a popular and effective solution in this area, given the absence of a final disposal system. The spent fuel cask system (dry cask method) provides a feasible solution to maintain spent fuel for 60 years before final disposal. Dry cask storage has many characteristics that make it attractive. It fulfills the safety requirements of the Nuclear Regulatory Commission (NRC) while providing modularity and flexibility to contractors. The HI-STORM overpack and MPC-32 canister are the main parts of the HI-STORM 100 dry cask storage system. These components remove heat from the system using natural circulation, requiring no human intervention. This is the characteristic that provides passive heat removal and low maintenance features in dry cask storage systems. To develop a thermal model for a dry cask storage system, the physics behind the system should be defined clearly. There are two natural circulation loops in the system; circulation of helium cools down the nuclear assemblies in the MPC, while circulation of air cools down the walls of the MPC. This work aims to develop a thermal model of the MPC-32 canister and HI-STORM overpack using the Multiphysics Object-Oriented Simulation Environment (MOOSE). MOOSE is an open-source framework developed by Idaho National Laboratory (INL) for multiscale, multiphysics simulations. In this study, we will investigate and demonstrate the thermal-hydraulics modeling capabilities of the MOOSE framework, including natural circulation, heat transfer, and porous flow.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2025

Depletion Analysis of a Generic Fast Spectrum Molten Salt Reactor Supporting Material Control and Accounting (Rev.1)

Advanced reactors are of interest for a variety of use scenarios, and there are numerous advanced reactor designs being considered, which includes molten salt reactors (MSRs). Depending on the design, advanced reactors may have more extensive material control and accounting (MC&A) processes than current Light Water Reactor (LWR) designs. This project evaluated the use of Monte Carlo simulations for generating information that could guide the development of MC&A approaches for MSRs. In particular, the current capabilities of MCNP version 6.3 internally coupled with CINDER’90 were assessed for a fast spectrum liquid fueled MSR with online fission product removal and refueling. The fission product removal and refueling was performed in batches, and a Python wrapper was developed to control the simulations and update the fuel composition.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
DOE OSTI2024

Deep Learning for Fish Identification from Sonar Data (CRADA 481 Final Report)

In eastern regions of the United States, the American eel is a species of management and regulatory concern because of significant population declines, despite the species’ previous abundance in all tributaries of rivers flowing into the Atlantic Ocean. The American eel is also a candidate for listing under the U.S. Endangered Species Act. While hydropower construction and operation are only one of several factors contributing to this population decline, such a listing could impose additional regulatory challenges for a large number of hydropower projects. In this CRADA project, we improved technologies for identifying migrating eels with the goal of reducing the cost and time required for future American eel hydropower impact assessment and mitigation studies, while maintaining accuracy. We built on results from a previous FOA project (FOA# DE-FOA-0001662), led by the Electric Power Research Institute (EPRI), which developed a highly accurate, deep-learning method for identifying migrating eels from imaging sonar data. The current study aimed to further optimize this deep-learning model, originally designed for image classification, and to develop an object detection software capable of identifying fish from sonar videos in real time, enabling the detection of events like fish migrations and specific species, such as the American eel, at hydropower dams. The data conversion algorithms were packaged as software with a graphical user interface, and the software is evaluated by external collaborators. We focused on the American eel in this project and explored the transferability of the developed deep learning models to the sea lamprey, given the similar body shape and swimming behavior between the two species.

13 HYDRO ENERGY↗
DOE OSTI2026

DER Cybersecurity Standards: Assessment and Gap Analysis

The purpose of this report is to share the comprehensive gap analysis of existing cybersecurity standards applicable to Distributed Energy Resources (DERs) within the electric power sector. This analysis aims to identify critical deficiencies in current standards, assess their alignment with industry needs, and provide actionable recommendations for enhancing cybersecurity measures. The scope encompasses various DER technologies, including solar, wind, energy storage, and hydrogen fuel cells, and emphasizes the significance of establishing robust cybersecurity frameworks and standards to safeguard these increasingly integrated systems. The report provides valuable insights for stakeholders in the DER ecosystem, including manufacturers, utilities, and regulators. It underscores the importance of continued development and refinement of cybersecurity standards to keep up with the technical advances in DERs and associated cybersecurity challenges. The analysis evaluated IEC, IEEE, ISA, ISO, and UL standards relevant to DER cybersecurity. Standards were assessed on their coverage of key requirements including data availability, integrity, confidentiality, access control, authentication, encryption, and system hardening. For each standard, the analysis assessed its alignment with current industry practices, regulatory compliance, effectiveness in addressing known risks, coverage of emerging risks, and how it promotes interoperability. The evaluation also considered potential integration challenges and barriers to adoption.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2022

Benchmarking Real-Time Control Platforms Using a Matlab/Simulink Coder with Applications in the Control of DC/AC Switched Power Converters

In the control of DC/AC switched power converters (SPC), one of the most important aspects to be considered is the selection of the real-time control platform. The real-time control platform must be able to meet the high performance efficiency and regulation requirements of the DC/AC SPC, as these typically operate at switching frequencies in the order of kHz to MHz. For this reason, the hardware characteristics of the ADC and PWM, and the processing capacity of the real-time control platform are of vital importance when implementing advanced digital controllers that maintain voltage and current levels within regulatory standards. In this context, we aimed to perform a comparative study of the computation times of different real-time control platforms when implementing different control strategies for DC/AC switched power converters. We also analyzed the impact of the real-time control platforms on the THD of the voltages generated by the DC/AC switched power converters. With the help of this paper, researchers and developers will have criteria to select which real-time control platform to use in real-time control for DC/AC SPC applications.

42 ENGINEERING↗
DOE OSTI2024

Comprehensive Genome-Wide Natural Variation and Expression Analysis of Tubby-like Proteins Gene Family in Brachypodium distachyon

The Tubby-like proteins (TLPs) gene family is a group of transcription factors found in both animals and plants. In this study, we identified twelve B. distachyon TLPs, divided into six groups based on conserved domains and evolutionary relationships. We predicted cis-regulatory elements involved in light, hormone, and biotic and abiotic stresses. The expression patterns in response to light and hormones revealed that BdTLP3, 4, 7, and 14 are involved in light responses, and BdTLP1 is involved in ABA responses. Furthermore, BdTLP2, 7, 9, and 13 are expressed throughout vegetative and reproductive stages, whereas BdTLP1, 3, 5, and 14 are expressed at germinating grains and early vegetative development, and BdTLP4, 6, 8, and 10 are expressed at the early reproduction stage. The natural variation in the eleven most diverged B. distachyon lines revealed high conservation levels of BdTLP1-6 to high variation in BdTLP7-14 proteins. Based on diversifying selection, we identified amino acids in BdTLP1, 3, 8, and 13, potentially substantially affecting protein functions. This analysis provided valuable information for further functional studies to understand the regulation, pathways involved, and mechanism of BdTLPs.

Plant Sciences↗
DOE OSTI2023

Coupling High-Throughput and Targeted Screening for Identification of Nonobvious Metabolic Engineering Targets

Identification of metabolic engineering targets is a fundamental challenge in strain development programs. While high-throughput (HTP) genetic engineering methodologies capable of generating vast diversity are being developed at a rapid rate, a majority of industrially interesting molecules cannot be screened at sufficient throughput to leverage these techniques. We propose a workflow that couples HTP screening of common precursors (e.g., amino acids) that can be screened either directly or by artificial biosensors, with low-throughput targeted validation of the molecule of interest to uncover nonintuitive beneficial metabolic engineering targets and combinations hereof. Using this workflow, we identified several nonobvious novel targets for improving p-coumaric acid (p-CA) and L -DOPA production from two large 4k gRNA libraries each deregulating 1000 metabolic genes in the yeast Saccharomyces cerevisiae. We initially screened yeast cells transformed with gRNA library plasmids for individual regulatory targets improving the production of l-tyrosine-derived betaxanthins, identifying 30 targets that increased intracellular betaxanthin content 3.5–5.7 fold. Hereafter, we screened the targets individually in a high-producing p-CA strain, narrowing down the targets to six that increased the secreted titer by up to 15%. To investigate whether any of the six targets could be additively combined to improve p-CA production further, we created a gRNA multiplexing library and subjected it to our proposed coupled workflow. The combination of regulating PYC1 and NTH2 simultaneously resulted in the highest (threefold) improvement of the betaxanthin content, and an additive trend was also observed in the p-CA strain. Lastly, we tested the initial 30 targets in a L -DOPA producing strain, identifying 10 targets that increased the secreted titer by up to 89%, further validating our screening by proxy workflow. This coupled approach is useful for strain development in the absence of direct HTP screening assays for products of interest.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Developing a Prototype Methodology to Rank CO2-EOR Wells and Assess Their Reuse Potential for Geologic Carbon Sequestration

This study presents a prototype methodology for evaluating the reuse potential of Class II CO₂-enhanced oil recovery (CO₂-EOR) wells as Class VI wells for geologic carbon sequestration. The approach focuses on assessing wellbore construction materials—casing, cement, tubing, and packers—based on U.S. Environmental Protection Agency (EPA) Class VI well conversion guidelines. Utilizing Python scripts and JSON representations, the methodology automates checks on digitized Texas Railroad Commission (TRRC) data to rank wells based on regulatory and integrity criteria. Key factors include casing integrity, cementing techniques, tubing compatibility, and packer selection. Due to limitations in digitized data, manual verification is required for certain sections. Future enhancements include incorporating non-digitized data via web scraping and machine learning. This research provides a practical framework for well owners and regulators, supporting informed decision-making for sustainable CO₂ storage.

carbon sequestration↗
DOE OSTI2023

Identification of conserved skeletal enhancers associated with craniosynostosis risk genes

Abstract Craniosynostosis, defined by premature fusion of one or multiple cranial sutures, is a common congenital defect affecting more than 1/2000 infants and results in restricted brain expansion. Single gene mutations account for 15%–20% of cases, largely as part of a syndrome, but the majority are nonsyndromic with complex underlying genetics. We hypothesized that the two noncoding genomic regions identified by a GWAS for craniosynostosis contain distal regulatory elements for the risk genes BMPER and BMP2. To identify such regulatory elements, we surveyed conserved noncoding sequences from both risk loci for enhancer activity in transgenic Danio rerio. We identified enhancers from both regions that direct expression to skeletal tissues, consistent with the endogenous expression of bmper and bmp2. For each locus, we also found a skeletal enhancer that also contains a sequence variant associated with craniosynostosis risk. We examined the activity of each enhancer during craniofacial development and found that the BMPER-associated enhancer is active in the restricted region of cartilage closely associated with frontal bone initiation. The same enhancer is active in mouse skeletal tissues, demonstrating evolutionarily conserved activity. Using enhanced yeast one-hybrid assays, we identified transcription factors that bind each enhancer and observed differential binding between alleles, implicating multiple signaling pathways. Our findings help unveil the genetic mechanism of the two craniosynostosis risk loci. More broadly, our combined in vivo approach is applicable to many complex genetic diseases to build a link between association studies and specific genetic mechanisms.

He(何璇), Xuan Anita (ORCID:0000000313221972)↗