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All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Announcing the Biomedical Data Translator: Initial Public Release

ABSTRACT The growing availability of biomedical data offers vast potential to improve human health, but the complexity and lack of integration of these datasets often limit their utility. To address this, the Biomedical Data Translator Consortium has developed an open‐source knowledge graph–based system—Translator—designed to integrate, harmonize, and make inferences over diverse biomedical data sources. We announce here Translator's initial public release and provide an overview of its architecture, standards, user interface, and core features. Translator employs a scalable, federated, knowledge graph framework for the integration of clinical, genomic, pharmacological, and other biomedical knowledge sources, enabling query retrieval, inference, and hypothesis generation. Translator's user interface is designed to support the exploration of knowledge relationships and the generation of insights, without requiring deep technical expertise and gradually revealing more detailed evidence, provenance, and confidence information, as needed by a given user. To demonstrate Translator's application and impact, we highlight features of the user interface in the context of three real‐world use cases: suggesting potential therapeutics for patients with rare disease; explaining the mechanism of action of a pipeline drug; and screening and validating drug candidates in a model organism. We discuss strengths and limitations of reasoning within a largely federated system and the need for rich concept modeling and deep provenance tracking. Finally, we outline future directions for enhancing Translator's functionality and expanding its data sources. Translator represents a significant step forward in making complex biomedical knowledge more accessible and actionable, aiming to accelerate translational research and improve patient care.

Research & Experimental Medicine↗
DOE OSTI2023

Chymotrypsin-like Elastase-1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin (AAT) deficiency is a rare disease affecting approximately 1 in 2000 White individuals with approximately 10% of these individuals developing AATD lung disease. This lung disease is marked by progressive alveolar loss despite the withdrawal of triggering agents such as cigarette smoke. Although the PiZZ genotype is the most common mutation, there are over 100 described variants making true population estimates difficult and AAT deficiency is typically diagnosed by reduced levels of AAT in the blood. Typically developing in the fourth and fifth decades of life, AAT-deficient lung disease is marked by progressive emphysema and is the fourth leading indication for lung transplantation. AAT augmentation therapy does not prevent disease progression making the development of new therapeutic approaches critical. Chymotrypsin-like elastase 1 (CELA1) is a serine protease synthesized and secreted by alveolar type 2 cells with a physiologic role in reducing postnatal lung elastance. At a molecular level, CELA1 binds and cleaves non-crosslinked, hydrophobic domains of tropoelastin, and its binding to lung elastin fibers is increased with strain—similar to other pancreatic elastases. CELA1 is neutralized by covalent binding with AAT, and Cela1 -/- mice were completely protected from emphysema in an antisense oligonucleotide model of AAT-deficient emphysema. This model, however, did not include any injury apart from administration of the antisense oligonucleotide with levels of emphysema exceeding that seen in mice with genetic ablation of 5 Serpina1 paralogues and subjected to tracheal lipopolysacharide or cigarette smoke. Here, we use this murine genetic model of AAT deficiency to test the role of the CELA1 gene in AAT-deficient emphysema using multiple models to show that CELA1 has a role in progressive airspace enlargement in AAT-deficiency independent of inflammation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Drosophila models to study causative genes for human rare intractable neurological diseases

Highlights: • Drosophila models targeting some ALS-causing genes are described. • Drosophila models targeting some CMT-causing genes are described. • Drosophila models targeting some Sotos syndrome-causing genes are described. • Genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. Drosophila is emerging as a convenient model for investigating human diseases. Functional homologues of almost 75% of human disease-related genes are found in Drosophila. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes defects in motoneurons. Charcot-Marie-Tooth disease (CMT) is one of the most commonly found inherited neuropathies affecting both motor and sensory neurons. No effective therapy has been established for either of these diseases. In this review, after overviewing ALS, Drosophila models targeting several ALS-causing genes, including TDP-43, FUS and Ubiquilin2, are described with their genetic interactants. Then, after overviewing CMT, examples of Drosophila models targeting several CMT-causing genes, including mitochondria-related genes and FIG 4, are also described with their genetic interactants. In addition, we introduce Sotos syndrome caused by mutations in the epigenetic regulator gene NSD1. Lastly, several genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. In the case of ALS and CMT that have many causative genes, it may be not practical to perform gene therapy for each of the many disease-causing genes. The possible uses of the common genes and pathways as novel diagnosis markers and effective therapeutic targets are discussed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Mondo: integrating disease terminology across communities

Precision medicine aims to enhance diagnosis, treatment, and prognosis by integrating multimodal data at the point of care. However, challenges arise due to the vast number of diseases, differing methods of classification, and conflicting terminological coding systems and practices used to represent molecular definitions of disease. This lack of interoperability artificially constrains the potential for diagnosis, clinical decision support, care outcome analysis, as well as data linkage across research domains to support the development or repurposing of therapeutics. There is a clear and pressing need for a unified system for managing disease entities⁠—including identifiers, synonyms, and definitions. To address these issues, we created the Mondo disease ontology—a community-driven, open-source, unified disease classification system that harmonizes diverse terminologies into a consistent, computable framework. Mondo integrates key medical and biomedical terminologies, including Online Mendelian Inheritance in Man (OMIM), Orphanet, Medical Subject Headings (MeSH), National Cancer Institute Thesaurus (NCIt), and more, to provide a comprehensive and accurate representation of disease concepts with fully provenanced and attributed links back to the sources. Mondo can be used as the handle for curation of gene–disease associations utilized in diagnostic applications, research applications such as computational phenotyping, and in clinical coding systems in clinical decision support by pointing the clinician to the numerous knowledge resources linked to the Mondo identifier. Mondo's community-centric approach, stewarded by the Monarch Initiative's expertise in ontologies, ensures that the ontology remains adaptable to the evolving needs of biomedical research and clinical communities, as well as the knowledge providers.

biomedical informatics↗
DOE OSTI2022

Warning Signs of Potential Black Swan Outbreaks in Infectious Disease

Black swan events in infectious disease describe rare but devastatingly large outbreaks. While experts are skeptical that such events are predictable, it might be possible to identify the warning signs of a black swan event. Specifically, following the initiation of an outbreak, key differentiating features could serve as alerts. Such features could be derived from meta-analyses of large outbreaks for multiple infectious diseases. We hypothesized there may be common features among the pathogen, environment, and host epidemiological triad that characterize an infectious disease black swan event. Using Los Alamos National Laboratory’s tool, Analytics for Investigation of Disease Outbreaks, we investigated historical disease outbreak information and anomalous events for several infectious diseases. By studying 32 different infectious diseases and global outbreaks, we observed that in the past 20–30 years, there have been potential black swan events in the majority of infectious diseases analyzed. Importantly, these potential black swan events cannot be attributed to the first introduction of the disease to a susceptible host population. This paper describes our observations and perspectives and illustrates the value of broad analysis of data across the infectious disease realm, providing insights that may not be possible when we focus on singular infectious agents or diseases. Data analytics could be developed to warn health authorities at the beginning of an outbreak of an impending black swan event. Such tools could complement traditional epidemiological modeling to help forecast future large outbreaks and facilitate timely warning and effective, targeted resource allocation for mitigation efforts.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Antimicrobial resistance and genomic characterization of Salmonella Dublin isolates in cattle from the United States

Salmonella enterica subspecies enterica serotype Dublin is a host-adapted serotype in cattle, associated with enteritis and systemic disease. The primary clinical manifestation of Salmonella Dublin infection in cattle, especially calves, is respiratory disease. While rare in humans, it can cause severe illness, including bacteremia, with hospitalization and death. In the United States, S . Dublin has become one of the most multidrug-resistant serotypes. The objective of this study was to characterize S . Dublin isolates from sick cattle by analyzing phenotypic and genotypic antimicrobial resistance (AMR) profiles, the presence of plasmids, and phylogenetic relationships. S . Dublin isolates (n = 140) were selected from submissions to the NVSL for Salmonella serotyping (2014–2017) from 21 states. Isolates were tested for susceptibility against 14 class-representative antimicrobial drugs. Resistance profiles were determined using the ABRicate with Resfinder and NCBI databases, AMRFinder and PointFinder. Plasmids were detected using ABRicate with PlasmidFinder. Phylogeny was determined using vSNP. We found 98% of the isolates were resistant to more than 4 antimicrobials. Only 1 isolate was pan-susceptible and had no predicted AMR genes. All S . Dublin isolates were susceptible to azithromycin and meropenem. They showed 96% resistance to sulfonamides, 97% to tetracyclines, 95% to aminoglycosides and 85% to beta-lactams. The most common AMR genes were: sulf2 and tetA (98.6%), aph(6)-Id (97.9%), aph(3’’)-Ib, (97.1%), floR (94.3%), and blaCMY-2 (85.7%). All quinolone resistant isolates presented mutations in gyr A. Ten plasmid types were identified among all isolates with IncA/C2, IncX1, and IncFII(S) being the most frequent. The S . Dublin isolates show low genomic genetic diversity. This study provided antimicrobial susceptibility and genomic insight into S . Dublin clinical isolates from cattle in the U.S. Further sequence analysis integrating food and human origin S . Dublin isolates may provide valuable insight on increased virulence observed in humans.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Cardiac Sarcoidosis

Purpose of Review: In this state-of-the-art review, we highlight our current understanding of diagnosis, assessment, and management of cardiac sarcoidosis (CS), focusing on recently published data and expert consensus statement guidelines. Recent Findings: Academic interest in cardiac sarcoidosis research has increased over the past decade along with increased clinical awareness among clinicians. In 2014, the Heart Rhythm Society published the first expert consensus statement on diagnosing and managing arrhythmias associated with CS. Cardiac magnetic resonance has emerged as a valuable tool both for diagnosing CS and predicting risk of life-threatening ventricular arrhythmias based on burden of late gadolinium enhancement. Cardiac fluorodeoxyglucose-positron emission tomography now plays a role in diagnosis, risk stratification, and assessing response to immunosuppressive therapy. Summary: Collaborative, multidisciplinary research efforts are needed to further our understanding of this rare, complex disease. Two large multicenter prospective registries—the international Cardiac Sarcoidosis Consortium and the Canadian Cardiac Sarcoidosis Research Group—are enrolling patients to help provide insights into the natural history of the disease and current treatment strategies. Future research should focus on randomized controlled trials comparing different treatment strategies and identifying and testing novel therapeutic agents.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Application of prophage sequence analysis to investigate a disease outbreak involving Salmonella Adjame, a rare serovar and implications for the population structure

Introduction Outbreak investigation of foodborne salmonellosis is hindered when the food source is contaminated by multiple strains of Salmonella , creating difficulties matching an incriminated organism recovered from patients with the specific strain in the suspect food. An outbreak of the rare Salmonella Adjame was caused by multiple strains of the organism as revealed by single-nucleotide polymorphism (SNP) variation. The use of highly discriminatory prophage analysis to characterize strains of Salmonella should enable a more precise strain characterization and aid the investigation of foodborne salmonellosis. Methods We have carried out genomic analysis of S. Adjame strains recovered during the course of a recent outbreak and compared them with other strains of the organism ( n = 38 strains), using SNPs to evaluate strain differences present in the core genome, and prophage sequence typing (PST) to evaluate the accessory genome. Phylogenetic analyses were performed using both total prophage content and conserved prophages. Results The PST analysis of the S. Adjame isolates showed a high degree of strain heterogeneity. We observed small clusters made up of 2-6 isolates ( n = 27) and singletons ( n = 11) in stark contrast with the three clusters observed by SNP analysis. In total, we detected 24 prophages of which only four were highly prevalent, namely: Entero_p88 (36/38 strains), Salmon_SEN34 (35/38 strains), Burkho_phiE255 (33/38 strains) and Edward_GF (28/38 strains). Despite the marked strain diversity seen with prophage analysis, the distribution of the four most common prophages matched the clustering observed using core genome. Discussion Mutations in the core and accessory genomes of S. Adjame have shed light on the evolutionary relationships among the Adjame strains and demonstrated a convergence of the variations observed in both fractions of the genome. We conclude that core and accessory genomes analyses should be adopted in foodborne bacteria outbreak investigations to provide a more accurate strain description and facilitate reliable matching of isolates from patients and incriminated food sources. The outcomes should translate to a better understanding of the microbial population structure and an 46 improved source attribution in foodborne illnesses.

Gao, Ruimin↗
DOE OSTI2021

Implication of rare genetic variants of NODAL and ACVR1B in congenital heart disease patients from Indian population

Highlights: • Screening of 300 CHD patients revealed two rare missense variants (p.P51L & p.D327E) in NODAL. • A novel missense variation p.M345I was identified in ACVR1B. • Bioinformatic analyses suggested that these variants could have deleterious role. • Three-dimensional modelling suggested conformation changes in the mutated proteins compared to wild-type. • In vitro studies demonstrated that missense variants affect the function of NODAL and ACVR1B. NODAL signaling plays an essential role in vertebrate embryonic patterning and heart development. Accumulating evidences suggest that genetic mutations in TGF-β/NODAL signaling pathway can cause congenital heart disease in humans. To investigate the implication of NODAL signaling in isolated cardiovascular malformation, we have screened 300 non-syndromic CHD cases and 200 controls for NODAL and ACVR1B by Sanger sequencing and identified two rare missense (c.152C > T; p.P51L and c.981 T > A; p.D327E) variants in NODAL and a novel missense variant c.1035G > A; p.M345I in ACVR1B. All these variants are absent in 200 controls. Three-dimensional protein-modelling demonstrates that both p.P51L and p.D327E variations of NODAL and p.M345I mutation of ACVR1B, affect the tertiary structure of respective proteins. Variants of NODAL (p.P51L and p.D327E) and ACVR1B (p.M345I), significantly reduce the transactivation of AR3-Luc, (CAGA){sub 12}-Luc and (SBE){sub 4}-Luc promoters. Moreover, qRT-PCR results have also deciphered a reduction in the expression of cardiac-enriched transcription factors namely Gata4, Nkx2-5, and Tbx5 in both the mutants of NODAL. Decreased expression of, Gata4, Nkx2-5, Tbx5, and lefty is observed in p.M345I mutant of ACVR1B as well. Additionally, reduced phosphorylation of SMAD2/3 in response to these variants, suggests impaired NODAL signaling and possibly responsible for defective cell fate decision and differentiation of cardiomyocytes leading to CHD phenotype.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Gait Characterization and Analysis of Hereditary Amyloidosis Associated with Transthyretin Patients: A Case Series

Hereditary amyloidosis associated with transthyretin (ATTRv), is a rare autosomal dominant disease characterized by length-dependent symmetric polyneuropathy that has gait impairment as one of its consequences. The gait pattern of V30M ATTRv amyloidosis patients has been described as similar to that of diabetic neuropathy, associated with steppage, but has never been quantitatively characterized. In this study we aim to characterize the gait pattern of patients with V30M ATTRv amyloidosis, thus providing information for a better understanding and potential for supporting diagnosis and disease progression evaluation. We present a case series in which we conducted two gait analyses, 18 months apart, of five V30M ATTRv amyloidosis patients using a 12-camera, marker based, optical system as well as six force platforms. Linear kinematics, ground reaction forces, and angular kinematics results are analyzed for all patients. All patients, except one, showed a delayed toe-off in the second assessment, as well as excessive pelvic rotation, hip extension and external transverse rotation and knee flexion (in stance and swing phases), along with reduced vertical and mediolateral ground reaction forces. The described gait anomalies are not clinically quantified; thus, gait analysis may contribute to the assessment of possible disease progression along with the clinical evaluation.

Vilas-Boas, Maria do Carmo (ORCID:000000025012789X↗
DOE OSTI2021

A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This “participant-derived xenograft” model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Harnessing Nanobodies for Precision Targeting of Proteoforms: Opportunities and Challenges in Therapeutics and Diagnostics

Proteoforms are biologically distinct yet structurally similar proteins that play key roles in driving disease progression but are rarely accounted for in the development of therapeutics and diagnostics. Nanobodies (Nbs) have emerged as a therapeutic and diagnostic “silver bullet” as they possess unique structural and functional attributes that offer advantages over traditional antibodies. One of the most profound advantages of Nbs is the heightened sensitivity and ability to distinguish subtle changes in the conformation of a given protein. Thus, Nbs have significant potential as therapeutic and diagnostic agents that can identify and distinguish specific pathological proteoforms that underlie a given disease. However, there remain significant challenges in obtaining sufficient quantities and purities of specific proteoform antigens that are required for engineering proteoform-specific Nbs. Recent advancements in chemical biology tools for precision proteoform synthesis have made this task feasible for the first time. In this perspective, we discuss the advantages and challenges associated with developing proteoform-specific Nbs and how success in this endeavor will significantly advance the fields of therapeutics and diagnostics.

Antigens↗
DOE OSTI2021

Decoding Cancer Variants of Unknown Significance for Helicase–Nuclease–RPA Complexes Orchestrating DNA Repair During Transcription and Replication

All tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. To objectively decode VUS, we mapped cancer sequence data and evolutionary trace (ET) scores onto crystallography and cryo-electron microscopy structures with variant impacts quantitated by evolutionary action (EA) measures. As tumors depend on helicases and nucleases to deal with transcription/replication stress, we targeted helicase–nuclease–RPA complexes: (1) XPB-XPD (within TFIIH), XPF-ERCC1, XPG, and RPA for transcription and nucleotide excision repair pathways and (2) BLM, EXO5, and RPA plus DNA2 for stalled replication fork restart. As validation, EA scoring predicts severe effects for most disease mutations, but disease mutants with low ET scores not only are likely destabilizing but also disrupt sophisticated allosteric mechanisms. For sites of disease mutations and VUS predicted to be severe, we found strong co-localization to ordered regions. Rare discrepancies highlighted the different survival requirements between disease and tumor mutations, as well as the value of examining proteins within complexes. In a genome-wide analysis of 33 cancer types, we found correlation between the number of mutations in each tumor and which pathways or functional processes in which the mutations occur, revealing different mutagenic routes to tumorigenesis. We also found upregulation of ancient genes including BLM, which supports a non-random and concerted cancer process: reversion to a unicellular, proliferation-uncontrolled, status by breaking multicellular constraints on cell division. Together, these genes and global analyses challenge the binary “driver” and “passenger” mutation paradigm, support a gradient impact as revealed by EA scoring from moderate to severe at a single gene level, and indicate reduced regulation as well as activity. The objective quantitative assessment of VUS scoring and gene overexpression in the context of functional interactions and pathways provides insights for biology, oncology, and precision medicine.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Distant-acting Enhancers in Development and Disease

Multiple converging lines of evidence from experimental and human genetic studies indicate that both common and rare sequence variants involving enhancers play major roles in Mendelian and complex human disease phenotypes. We use a combination of sequence-based molecular approaches including chromatin mapping and synthesis-enabled modification of enhancer sequences, large-scale transgenic mouse studies (http://enhancer.lbl.gov), and CRISPR genome editing in the mouse model to study the in vivofunction of enhancers in developmental, evolutionary, and disease-related processes. Using examples from our ongoing work, I will illustrate how these methods provide insight into the function and evolution of distant-acting regulatory sequences and offer a starting point for understanding their role in human disease. I will discuss how improved in vivo mouse assays can be used to study candidate pathogenic human mutations in enhancers at scale, revealing the extent to which human genetic studies alone can be insufficient to identify truly causal mutations in enhancers. I will also show how such assays can be used to explore the sensitivity of enhancers that are extremely conserved ("ultraconserved") in evolution to mutations, revealing a remarkable functional robustness to sequence changes that contrasts with apparent evolutionary constraints.

Visel, A↗
DOE OSTI2024

Novel mutation leading to splice donor loss in a conserved site of DMD gene causes Duchenne muscular dystrophy with cryptorchidism

Background As one of the most common congenital abnormalities in male births, cryptorchidism has been found to have a polygenic aetiology according to previous studies of common variants. However, little is known about genetic predisposition of rare variants for cryptorchidism, since rare variants have larger effective size on diseases than common variants. Methods In this study, a cohort of 115 Chinese probands with cryptorchidism was analysed using whole-genome sequencing, alongside 19 parental controls and 2136 unaffected men. Additionally, CRISPR-Cas9 editing of a conserved variant was performed in a mouse model, with MRI screening used to observe the phenotype. Results In 30 of 115 patients (26.1%), we identified four novel genes ( ARSH , DMD , MAGEA4 and SHROOM2 ) affecting at least five unrelated patients and four known genes ( USP9Y , UBA1 , BCORL1 and KDM6A ) with the candidate rare pathogenic variants affecting at least two cases. Burden tests of rare variants revealed the genome-wide significances for newly identified genes (p<2.5×10 −6 ) under the Bonferroni correction. Surprisingly, novel and known genes were mainly found on X chromosome (seven on X and one on Y) and all rare X-chromosomal segregating variants exhibited a maternal inheritance rather than de novo origin. CRISPR-Cas9 mouse modelling of a splice donor loss variant in DMD (NC_000023.11:g.32454661C>G), which resides in a conserved site across vertebrates, replicated bilateral cryptorchidism phenotypes, confirmed by MRI at 4 and 10 weeks. The movement tests further revealed symptoms of Duchenne muscular dystrophy (DMD) in transgenic mice. Conclusion Our results revealed the role of the DMD gene mutation in causing cryptorchidism. The results also suggest that maternal-X inheritance of pathogenic defects could have a predominant role in the development of cryptorchidism.

Chen, Jianhai (ORCID:0000000300932003)↗
DOE OSTI2025

Precipitation of gadolinium from magnetic resonance imaging contrast agents may be the Brass tacks of toxicity

The formation of gadolinium-rich nanoparticles in multiple tissues from intravenous magnetic resonance imaging contrast agents may be the initial step in rare earth metallosis. The mechanism of gadolinium-induced diseases is poorly understood, as is how these characteristic nanoparticles are formed. Gadolinium deposition has been observed with all magnetic resonance imaging contrast agent brands. Aside from endogenous metals and acidic conditions, little attention has been paid to the role of the biological milieu in the degradation of magnetic resonance imaging contrast agents into nanoparticles. Herein, we describe the decomposition of the commercial magnetic resonance imaging contrast agents Omniscan and Dotarem in the presence of oxalic acid, a well-known endogenous compound. Omniscan dechelated rapidly and preluded measurement by the means available, while Dotarem underwent a two-step decomposition process. The decomposition of both magnetic resonance imaging contrast agents by oxalic acid formed gadolinium oxalate (Gd 2 [C 2 O 4 ] 3 , Gd 2 Ox 3 ). Furthermore, both observed steps of the Dotarem reaction involved the associative addition of oxalic acid. Adding protein (bovine serum albumin) increased the rate of dechelation. Displacement reactions could occur at lysosomal pH. Through these studies, we have demonstrated that magnetic resonance imaging contrast agents can be dissociated by endogenous molecules, thus illustrating a metric by which gadolinium-based contrast agents (GBCAs) might be destabilized in vivo.

Gadodiamide↗
DOE OSTI2023

Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability

Accurate predictions of the pathogenicity of mutations associated with genetic diseases are key to the success of precision medicine. Inherited missense mutations in the myocilin (MYOC) gene, within its olfactomedin (OLF) domain, constitute the strongest genetic link to primary open-angle glaucoma via a toxic gain of function, and thus MYOC is an attractive precision-medicine target. However, not all mutations in MYOC cause glaucoma, and common variants are expected to be neutral polymorphisms. The Genome Aggregation Database (gnomAD) lists ~100 missense variants documented within OLF, all of which are relatively rare (allele frequency <0.001%) and nearly all are of unknown pathogenicity. To distinguish disease-causing OLF variants from benign OLF variants, we first characterized the most prevalent population-based variants using a suite of cellular and biophysical assays, and identified two variants with features of aggregation-prone familial disease variants. Next, we considered all available biochemical and clinical data to demonstrate that pathogenic and benign variants can be differentiated statistically based on a single metric: the thermal stability of OLF. Our results motivate genotyping MYOC in patients for clinical monitoring of this widespread, painless and irreversible ocular disease.

59 BASIC BIOLOGICAL SCIENCES↗