Selected Grantee Publications
Spatiotemporal Image Reconstruction to Enable High-Frame-Rate Dynamic Photoacoustic Tomography With Rotating-Gantry Volumetric Imagers
Cam et al., Journal of Biomedical Optics . 2024.
https://pubmed.ncbi.nlm.nih.gov/38249994
Dynamic photoacoustic computed tomography (PACT) is a valuable imaging technique for monitoring physiological processes. However, the current imaging techniques are often limited to two-dimensional spatial imaging. While PACT imagers capable of taking three-dimensional spatial images are commercially available, these systems have substantial limitations. Typically, the data are acquired sequentially rather than simultaneously at all views. The objects being imaged are dynamic and can vary during this process; as such, image reconstruction is inherently difficult, and the result is often incomplete. Cam et al. propose an image reconstruction method that can address these challenges and enable volumetric dynamic PACT imaging using existing preclinical imagers, which has the potential to significantly advance preclinical research and facilitate the monitoring of critical physiological biomarkers. Supported by ORIP (R44OD023029) and NIBIB.
Synthetic Protein Circuits for Programmable Control of Mammalian Cell Death
Xia et al., Cell. 2024.
https://pubmed.ncbi.nlm.nih.gov/38657604/
Natural cell-death pathways have been shown to eliminate harmful cells and shape immunity. Researchers used synthetic protein-level cell-death circuits, collectively termed “synpoptosis” circuits, to proteolytically regulate engineered executioner proteins and mammalian cell death. They show that the circuits direct cell death modes, respond to combinations of protease inputs, and selectively eliminate target cells. This work provides a foundation for programmable control of mammalian cell death. Future studies could focus on programmable control of cell death in various contexts, including cancer, senescence, fibrosis, autoimmunity, and infection. Supported by ORIP (F30OD036190) and NIBIB.
Time of Sample Collection Is Critical for the Replicability of Microbiome Analyses
Allaband et al., Nature Metabolism. 2024.
https://pubmed.ncbi.nlm.nih.gov/38951660/
Lack of replicability remains a challenge in microbiome studies. As the microbiome field moves from descriptive and associative research to mechanistic and interventional studies, being able to account for all confounding variables in the experimental design will be critical. Researchers conducted a retrospective analysis of 16S amplicon sequencing studies in male mice. They report that sample collection time affects the conclusions drawn from microbiome studies. The lack of consistency in the time of sample collection could help explain poor cross-study replicability in microbiome research. The effect of diurnal rhythms on the outcomes and study designs of other fields is unknown but is likely significant. Supported by ORIP (T32OD017863), NCATS, NCI, NHLBI, NIAAA, NIAID, NIBIB, NIDDK, and NIGMS.
The Monarch Initiative in 2024: An Analytic Platform Integrating Phenotypes, Genes and Diseases Across Species
Putman et al., Nucleic Acids Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/38000386/
The Monarch Initiative aims to bridge the gap between the genetic variations, environmental determinants, and phenotypic outcomes critical for translational research. The Monarch app provides researchers access to curated data sets with information on genes, phenotypes, and diseases across species and advanced analysis tools for such diverse applications as variant prioritization, deep phenotyping, and patient profile matching. Researchers describe upgrades to the app, including scalable cloud-based infrastructure, simplified data ingestion and knowledge graph integration systems, enhanced data mapping and integration standards, and a new user interface with novel search and graph navigation features. A customized plugin for OpenAI’s ChatGPT allows the use of large language models to interrogate knowledge in the Monarch graph and increase the reliability of the responses of Monarch’s analytic tools. These upgrades will enhance clinical diagnosis and the understanding of disease mechanisms. Supported by ORIP (R24OD011883), NLM, and NHGRI.
Anti–Human Immunodeficiency Virus‑1 Activity of MoMo30 Protein Isolated from the Traditional African Medicinal Plant Momordica balsamina
Khan et al., Virology Journal. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035133/
Momordica balsamina has been reported to produce a ribosome-inactivating protein with anti‑HIV-1 activity and is commonly used by traditional African healers for treatment of HIV. Investigators characterized the mechanism of action of the MoMo30 protein, as well as the sequence of the protein-coding gene. They reported that MoMo30 functions as a lectin or carbohydrate-binding agent (CBA) and inhibits HIV-1 at nanomolar levels, with minimal cellular toxicity at inhibitory levels. CBAs can block the binding of envelope glycoproteins with their target receptors on cells. Thus, this protein could represent a potential new treatment strategy for HIV. Supported by ORIP (R24OD010947), NCI, NIGMS, and NIMHD.
Naturally Occurring Osteochondrosis Latens Lesions Identified by Quantitative and Morphological 10.5 T MRI in Pigs
Armstrong et al., Journal of Orthopaedic Research. 2023.
https://pubmed.ncbi.nlm.nih.gov/35716161/
Juvenile osteochondritis dissecans (JOCD) is a pediatric orthopedic disorder that is associated with pain and gait deficits. JOCD lesions form in the knee, elbow, and ankle joints and can progress to early-onset osteoarthritis. In this study, researchers used a noninvasive magnetic resonance imaging (MRI) method to identify naturally occurring lesions in intact knee and elbow joints of juvenile pigs. This work can be applied to noninvasive identification and monitoring of early JOCD lesions and determination of risk factors that contribute to their progression in children. Supported by ORIP (K01OD021293, T32OD010993), NIAMS, and NIBIB.
Gigapixel Imaging With a Novel Multi-Camera Array Microscope
Thomson et al., eLife. 2022.
https://www.doi.org/10.7554/eLife.74988
The dynamics of living organisms are organized across many spatial scales. The investigators created assembled a scalable multi-camera array microscope (MCAM) that enables comprehensive high-resolution, large field-of-view recording from multiple spatial scales simultaneously, ranging from structures that approach the cellular scale to large-group behavioral dynamics. By collecting data from up to 96 cameras, they computationally generated gigapixel-scale images and movies with a field of view over hundreds of square centimeters at an optical resolution of 18 µm. This system allows the team to observe the behavior and fine anatomical features of numerous freely moving model organisms on multiple spatial scales (e.g., larval zebrafish, fruit flies, slime mold). Overall, by removing the bottlenecks imposed by single-camera image acquisition systems, the MCAM provides a powerful platform for investigating detailed biological features and behavioral processes of small model organisms. Supported by ORIP (R44OD024879), NIEHS, NCI, and NIBIB.
Profiling Development of Abdominal Organs in the Pig
Gabriel et al., Scientific Reports. 2022.
https://www.doi.org/10.1038/s41598-022-19960-5
The pig is a model system for studying human development and disease due to its similarities to human anatomy, physiology, size, and genome. Moreover, advances in CRISPR gene editing have made genetically engineered pigs a viable model for the study of human pathologies and congenital anomalies. However, a detailed atlas illustrating pig development is necessary for identifying and modeling developmental defects. Here, the authors describe normal development of the pig abdominal system (i.e., kidney, liver, pancreas, spleen, adrenal glands, bowel, gonads) and compare them with congenital defects that can arise in gene-edited SAP130 mutant pigs. This atlas and the methods described here can be used as tools for identifying developmental pathologies of the abdominal organs in the pig at different stages of development. Supported by ORIP (U42OD011140), NHLBI, NIAID, NIBIB, NICHD, and NINDS.
Mineralocorticoid Receptor Blockade Normalizes Coronary Resistance in Obese Swine Independent of Functional Alterations in Kv Channels
Goodwill et al., Basic Research in Cardiology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34018061/
Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening. Supported by ORIP (U42OD011140, S10OD023438), NHLBI, and NIBIB.
MRI Characteristics of Japanese Macaque Encephalomyelitis (JME): Comparison to Human Diseases
Tagge et al., Journal of Neuroimaging. 2021.
https://onlinelibrary.wiley.com/doi/10.1111/jon.12868
Magnetic resonance imaging data (MRI) were obtained from 114 Japanese macaques, including 30 animals of both sexes that presented with neurological signs of Japanese macaque encephalomyelitis (JME). Quantitative estimates of blood-brain barrier permeability to gadolinium-based-contrast agent (GBCA) were obtained in acute, GBCA-enhancing lesions, and longitudinal imaging data were acquired for 15 JME animals. Intense, focal neuroinflammation was a key MRI finding in JME. Several features of JME compare directly to human inflammatory demyelinating diseases. The development and validation of noninvasive imaging biomarkers in JME provides the potential to improve diagnostic specificity and contribute to the understanding of human demyelinating diseases. Supported by ORIP (P51OD011092, S10OD018224), NINDS, and NIBIB.