Outcomes of Hospital-Acquired Hypernatremia.

BACKGROUND: Hospital-acquired hypernatremia is highly prevalent, overlooked, and associated with unfavorable consequences. There are limited studies examining the outcomes and discharge dispositions of various levels of hospital-acquired hypernatremia in patients with or without CKD. METHODS: We conducted an observational retrospective cohort study, and we analyzed the data of 1,728,141 patients extracted from the Cerner Health Facts database (January 1, 2000, to June 30, 2018). In this report, we investigated the association between hospital-acquired hypernatremia (serum sodium [Na] levels >145 mEq/L) and in-hospital mortality or discharge dispositions with kidney function status at admission using adjusted multinomial regression models. RESULTS: Of all hospitalized patients, 6% developed hypernatremia after hospital admission. The incidence of in-hospital mortality was 12% and 1% in patients with hypernatremia and normonatremia, respectively. The risk of all outcomes was significantly greater for serum Na >145 mEq/L compared with the reference interval (serum Na, 135-145 mEq/L). In patients with hypernatremia, odds ratios (95% confidence interval) for in-hospital mortality, discharge to hospice, and discharge to nursing facilities were 14.04 (13.71 to 14.38), 4.35 (4.14 to 4.57), and 3.88 (3.82 to 3.94), respectively ( P < 0.001, for all). Patients with eGFR (Chronic Kidney Disease Epidemiology Collaboration) 60-89 ml/min per 1.73 m 2 and normonatremia had the lowest odds ratio for in-hospital mortality (1.60 [1.52 to 1.70]). CONCLUSIONS: Hospital-acquired hypernatremia is associated with in-hospital mortality and discharge to hospice or to nursing facilities in all stages of CKD.

Toxicology knowledge graph for structural birth defects.

BACKGROUND: Birth defects are functional and structural abnormalities that impact about 1 in 33 births in the United States. They have been attributed to genetic and other factors such as drugs, cosmetics, food, and environmental pollutants during pregnancy, but for most birth defects there are no known causes. METHODS: To further characterize associations between small molecule compounds and their potential to induce specific birth abnormalities, we gathered knowledge from multiple sources to construct a reproductive toxicity Knowledge Graph (ReproTox-KG) with a focus on associations between birth defects, drugs, and genes. Specifically, we gathered data from drug/birth-defect associations from co-mentions in published abstracts, gene/birth-defect associations from genetic studies, drug- and preclinical-compound-induced gene expression changes in cell lines, known drug targets, genetic burden scores for human genes, and placental crossing scores for small molecules. RESULTS: Using ReproTox-KG and semi-supervised learning (SSL), we scored >30,000 preclinical small molecules for their potential to cross the placenta and induce birth defects, and identified >500 birth-defect/gene/drug cliques that can be used to explain molecular mechanisms for drug-induced birth defects. The ReproTox-KG can be accessed via a web-based user interface available at https://maayanlab.cloud/reprotox-kg . This site enables users to explore the associations between birth defects, approved and preclinical drugs, and all human genes. CONCLUSIONS: ReproTox-KG provides a resource for exploring knowledge about the molecular mechanisms of birth defects with the potential of predicting the likelihood of genes and preclinical small molecules to induce birth defects.

While birth defects are common, for most birth defects there are no known causes. During pregnancy, developing babies are exposed to drugs, cosmetics, food, and environmental pollutants that may cause birth defects. However, exactly how these environmental factors are involved in producing birth defects is difficult to discern. Also, birth defects can be a consequence of the genes inherited from the parents. We combined general data about human genes and drugs with specific data previously implicating genes and drugs in inducing birth defects to create a knowledge graph representation that connects genes, drugs, and birth defects. This knowledge graph can be used to explore new links that may explain why birth defects occur, particularly those that result from a combination of inherited and environmental influences.

Pharos 2023: an integrated resource for the understudied human proteome.

The Illuminating the Druggable Genome (IDG) project aims to improve our understanding of understudied proteins and our ability to study them in the context of disease biology by perturbing them with small molecules, biologics, or other therapeutic modalities. Two main products from the IDG effort are the Target Central Resource Database (TCRD) (http://juniper.health.unm.edu/tcrd/), which curates and aggregates information, and Pharos (https://pharos.nih.gov/), a web interface for fusers to extract and visualize data from TCRD. Since the 2021 release, TCRD/Pharos has focused on developing visualization and analysis tools that help reveal higher-level patterns in the underlying data. The current iterations of TCRD and Pharos enable users to perform enrichment calculations based on subsets of targets, diseases, or ligands and to create interactive heat maps and UpSet charts of many types of annotations. Using several examples, we show how to address disease biology and drug discovery questions through enrichment calculations and UpSet charts.

DrugCentral 2023 extends human clinical data and integrates veterinary drugs.

DrugCentral monitors new drug approvals and standardizes drug information. The current update contains 285 drugs (131 for human use). New additions include: (i) the integration of veterinary drugs (154 for animal use only), (ii) the addition of 66 documented off-label uses and iii) the identification of adverse drug events from pharmacovigilance data for pediatric and geriatric patients. Additional enhancements include chemical substructure searching using SMILES and 'Target Cards' based on UniProt accession codes. Statistics of interests include the following: (i) 60% of the covered drugs are on-market drugs with expired patent and exclusivity coverage, 17% are off-market, and 23% are on-market drugs with active patents and exclusivity coverage; (ii) 59% of the drugs are oral, 33% are parenteral and 18% topical, at the level of the active ingredients; (iii) only 3% of all drugs are for animal use only; however, 61% of the veterinary drugs are also approved for human use; (iv) dogs, cats and horses are by far the most represented target species for veterinary drugs; (v) the physicochemical property profile of animal drugs is very similar to that of human drugs. Use cases include azaperone, the only sedative approved for swine, and ruxolitinib, a Janus kinase inhibitor.

Hypernatremia in Hospitalized Patients: A Large Population-Based Study.

Background: Hypernatremia is a frequently encountered electrolyte disorder in hospitalized patients. Controversies still exist over the relationship between hypernatremia and its outcomes in hospitalized patients. This study examines the relationship of hypernatremia to outcomes among hospitalized patients and the extent to which this relationship varies by kidney function and age. Methods: We conducted an observational study to investigate the association between hypernatremia, eGFR, and age at hospital admission and in-hospital mortality, and discharge dispositions. We analyzed the data of 1.9 million patients extracted from the Cerner Health Facts databases (2000-2018). Adjusted multinomial regression models were used to estimate the relationship of hypernatremia to outcomes of hospitalized patients. Results: Of all hospitalized patients, 3% had serum sodium (Na) >145 mEq/L at hospital admission. Incidence of in-hospital mortality was 12% and 2% in hyper- and normonatremic patients, respectively. The risk of all outcomes increased significantly for Na >155 mEq/L compared with the reference interval of Na=135-145 mEq/L. Odds ratios (95% confidence intervals) for in-hospital mortality and discharge to a hospice or nursing facility were 34.41 (30.59-38.71), 21.14 (17.53-25.5), and 12.21 (10.95-13.61), respectively (all P<0.001). In adjusted models, we found that the association between Na and disposition was modified by eGFR (P<0.001) and by age (P<0.001). Sensitivity analyses were performed using the eGFR equation without race as a covariate, and the inferences did not substantially change. In all hypernatremic groups, patients aged 76-89 and ≥90 had higher odds of in-hospital mortality compared with younger patients (all P<0.001). Conclusions: Hypernatremia was significantly associated with in-hospital mortality and discharge to a hospice or nursing facility. The risk of in-hospital mortality and other outcomes was highest among those with Na >155 mEq/L. This work demonstrates that hypernatremia is an important factor related to discharge disposition and supports the need to study whether protocolized treatment of hypernatremia improves outcomes.

CACHE (Critical Assessment of Computational Hit-finding Experiments): A public-private partnership benchmarking initiative to enable the development of computational methods for hit-finding.

One aspirational goal of computational chemistry is to predict potent and drug-like binders for any protein, such that only those that bind are synthesized. In this Roadmap, we describe the launch of Critical Assessment of Computational Hit-finding Experiments (CACHE), a public benchmarking project to compare and improve small molecule hit-finding algorithms through cycles of prediction and experimental testing. Participants will predict small molecule binders for new and biologically relevant protein targets representing different prediction scenarios. Predicted compounds will be tested rigorously in an experimental hub, and all predicted binders as well as all experimental screening data, including the chemical structures of experimentally tested compounds, will be made publicly available, and not subject to any intellectual property restrictions. The ability of a range of computational approaches to find novel binders will be evaluated, compared, and openly published. CACHE will launch 3 new benchmarking exercises every year. The outcomes will be better prediction methods, new small molecule binders for target proteins of importance for fundamental biology or drug discovery, and a major technological step towards achieving the goal of Target 2035, a global initiative to identify pharmacological probes for all human proteins.

A Comprehensive COVID-19 Daily News and Medical Literature Briefing to Inform Health Care and Policy in New Mexico: Implementation Study.

BACKGROUND: On March 11, 2020, the New Mexico Governor declared a public health emergency in response to the COVID-19 pandemic. The New Mexico medical advisory team contacted University of New Mexico (UNM) faculty to form a team to consolidate growing information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease to facilitate New Mexico's pandemic management. Thus, faculty, physicians, staff, graduate students, and medical students created the "UNM Global Health COVID-19 Intelligence Briefing." OBJECTIVE: In this paper, we sought to (1) share how to create an informative briefing to guide public policy and medical practice and manage information overload with rapidly evolving scientific evidence; (2) determine the qualitative usefulness of the briefing to its readers; and (3) determine the qualitative effect this project has had on virtual medical education. METHODS: Microsoft Teams was used for manual and automated capture of COVID-19 articles and composition of briefings. Multilevel triaging saved impactful articles to be reviewed, and priority was placed on randomized controlled studies, meta-analyses, systematic reviews, practice guidelines, and information on health care and policy response to COVID-19. The finalized briefing was disseminated by email, a listserv, and posted on the UNM digital repository. A survey was sent to readers to determine briefing usefulness and whether it led to policy or medical practice changes. Medical students, unable to partake in direct patient care, proposed to the School of Medicine that involvement in the briefing should count as course credit, which was approved. The maintenance of medical student involvement in the briefings as well as this publication was led by medical students. RESULTS: An average of 456 articles were assessed daily. The briefings reached approximately 1000 people by email and listserv directly, with an unknown amount of forwarding. Digital repository tracking showed 5047 downloads across 116 countries as of July 5, 2020. The survey found 108 (95%) of 114 participants gained relevant knowledge, 90 (79%) believed it decreased misinformation, 27 (24%) used the briefing as their primary source of information, and 90 (79%) forwarded it to colleagues. Specific and impactful public policy decisions were informed based on the briefing. Medical students reported that the project allowed them to improve on their scientific literature assessment, stay current on the pandemic, and serve their community. CONCLUSIONS: The COVID-19 briefings succeeded in informing and guiding New Mexico policy and clinical practice. The project received positive feedback from the community and was shown to decrease information burden and misinformation. The virtual platforms allowed for the continuation of medical education. Variability in subject matter expertise was addressed with training, standardized article selection criteria, and collaborative editing led by faculty.

Getting Started with the IDG KMC Datasets and Tools.

The Illuminating the Druggable Genome (IDG) consortium is a National Institutes of Health (NIH) Common Fund program designed to enhance our knowledge of under-studied proteins, more specifically, proteins unannotated within the three most commonly drug-targeted protein families: G-protein coupled receptors, ion channels, and protein kinases. Since 2014, the IDG Knowledge Management Center (IDG-KMC) has generated several open-access datasets and resources that jointly serve as a highly translational machine-learning-ready knowledgebase focused on human protein-coding genes and their products. The goal of the IDG-KMC is to develop comprehensive integrated knowledge for the druggable genome to illuminate the uncharacterized or poorly annotated portion of the druggable genome. The tools derived from the IDG-KMC provide either user-friendly visualizations or ways to impute the knowledge about potential targets using machine learning strategies. In the following protocols, we describe how to use each web-based tool to accelerate illumination in under-studied proteins. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Interacting with the Pharos user interface Basic Protocol 2: Accessing the data in Harmonizome Basic Protocol 3: The ARCHS4 resource Basic Protocol 4: Making predictions about gene function with PrismExp Basic Protocol 5: Using Geneshot to illuminate knowledge about under-studied targets Basic Protocol 6: Exploring under-studied targets with TIN-X Basic Protocol 7: Interacting with the DrugCentral user interface Basic Protocol 8: Estimating Anti-SARS-CoV-2 activities with DrugCentral REDIAL-2020 Basic Protocol 9: Drug Set Enrichment Analysis using Drugmonizome Basic Protocol 10: The Drugmonizome-ML Appyter Basic Protocol 11: The Harmonizome-ML Appyter Basic Protocol 12: GWAS target illumination with TIGA Basic Protocol 13: Prioritizing kinases for lists of proteins and phosphoproteins with KEA3 Basic Protocol 14: Converting PubMed searches to drug sets with the DrugShot Appyter.

High performance implementation of the hierarchical likelihood for generalized linear mixed models: an application to estimate the potassium reference range in massive electronic health records datasets.

BACKGROUND: Converting electronic health record (EHR) entries to useful clinical inferences requires one to address the poor scalability of existing implementations of Generalized Linear Mixed Models (GLMM) for repeated measures. The major computational bottleneck concerns the numerical evaluation of multivariable integrals, which even for the simplest EHR analyses may involve millions of dimensions (one for each patient). The hierarchical likelihood (h-lik) approach to GLMMs is a methodologically rigorous framework for the estimation of GLMMs that is based on the Laplace Approximation (LA), which replaces integration with numerical optimization, and thus scales very well with dimensionality. METHODS: We present a high-performance, direct implementation of the h-lik for GLMMs in the R package TMB. Using this approach, we examined the relation of repeated serum potassium measurements and survival in the Cerner Real World Data (CRWD) EHR database. Analyzing this data requires the evaluation of an integral in over 3 million dimensions, putting this problem beyond the reach of conventional approaches. We also assessed the scalability and accuracy of LA in smaller samples of 1 and 10% size of the full dataset that were analyzed via the a) original, interconnected Generalized Linear Models (iGLM), approach to h-lik, b) Adaptive Gaussian Hermite (AGH) and c) the gold standard for multivariate integration Markov Chain Monte Carlo (MCMC). RESULTS: Random effects estimates generated by the LA were within 10% of the values obtained by the iGLMs, AGH and MCMC techniques. The H-lik approach was 4-30 times faster than AGH and nearly 800 times faster than MCMC. The major clinical inferences in this problem are the establishment of the non-linear relationship between the potassium level and the risk of mortality, as well as estimates of the individual and health care facility sources of variations for mortality risk in CRWD. CONCLUSIONS: We found that the direct implementation of the h-lik offers a computationally efficient, numerically accurate approach for the analysis of extremely large, real world repeated measures data via the h-lik approach to GLMMs. The clinical inference from our analysis may guide choices of treatment thresholds for treating potassium disorders in the clinic.

TIGA: target illumination GWAS analytics.

MOTIVATION: Genome-wide association studies can reveal important genotype-phenotype associations; however, data quality and interpretability issues must be addressed. For drug discovery scientists seeking to prioritize targets based on the available evidence, these issues go beyond the single study. RESULTS: Here, we describe rational ranking, filtering and interpretation of inferred gene-trait associations and data aggregation across studies by leveraging existing curation and harmonization efforts. Each gene-trait association is evaluated for confidence, with scores derived solely from aggregated statistics, linking a protein-coding gene and phenotype. We propose a method for assessing confidence in gene-trait associations from evidence aggregated across studies, including a bibliometric assessment of scientific consensus based on the iCite relative citation ratio, and meanRank scores, to aggregate multivariate evidence.This method, intended for drug target hypothesis generation, scoring and ranking, has been implemented as an analytical pipeline, available as open source, with public datasets of results, and a web application designed for usability by drug discovery scientists. AVAILABILITY AND IMPLEMENTATION: Web application, datasets and source code via https://unmtid-shinyapps.net/tiga/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DrugCentral 2021 supports drug discovery and repositioning.

DrugCentral is a public resource (http://drugcentral.org) that serves the scientific community by providing up-to-date drug information, as described in previous papers. The current release includes 109 newly approved (October 2018 through March 2020) active pharmaceutical ingredients in the US, Europe, Japan and other countries; and two molecular entities (e.g. mefuparib) of interest for COVID19. New additions include a set of pharmacokinetic properties for ∼1000 drugs, and a sex-based separation of side effects, processed from FAERS (FDA Adverse Event Reporting System); as well as a drug repositioning prioritization scheme based on the market availability and intellectual property rights forFDA approved drugs. In the context of the COVID19 pandemic, we also incorporated REDIAL-2020, a machine learning platform that estimates anti-SARS-CoV-2 activities, as well as the 'drugs in news' feature offers a brief enumeration of the most interesting drugs at the present moment. The full database dump and data files are available for download from the DrugCentral web portal.

TCRD and Pharos 2021: mining the human proteome for disease biology.

In 2014, the National Institutes of Health (NIH) initiated the Illuminating the Druggable Genome (IDG) program to identify and improve our understanding of poorly characterized proteins that can potentially be modulated using small molecules or biologics. Two resources produced from these efforts are: The Target Central Resource Database (TCRD) (http://juniper.health.unm.edu/tcrd/) and Pharos (https://pharos.nih.gov/), a web interface to browse the TCRD. The ultimate goal of these resources is to highlight and facilitate research into currently understudied proteins, by aggregating a multitude of data sources, and ranking targets based on the amount of data available, and presenting data in machine learning ready format. Since the 2017 release, both TCRD and Pharos have produced two major releases, which have incorporated or expanded an additional 25 data sources. Recently incorporated data types include human and viral-human protein-protein interactions, protein-disease and protein-phenotype associations, and drug-induced gene signatures, among others. These aggregated data have enabled us to generate new visualizations and content sections in Pharos, in order to empower users to find new areas of study in the druggable genome.

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19.

The urgent need for a cure for early phase COVID-19 infected patients critically underlines drug repositioning strategies able to efficiently identify new and reliable treatments by merging computational, experimental, and pharmacokinetic expertise. Here we report new potential therapeutics for COVID-19 identified with a combined virtual and experimental screening strategy and selected among already approved drugs. We used hydroxychloroquine (HCQ), one of the most studied drugs in current clinical trials, as a reference template to screen for structural similarity against a library of almost 4000 approved drugs. The top-ranked drugs, based on structural similarity to HCQ, were selected for in vitro antiviral assessment. Among the selected drugs, both zuclopenthixol and nebivolol efficiently block SARS-CoV-2 infection with EC50 values in the low micromolar range, as confirmed by independent experiments. The anti-SARS-CoV-2 potential of ambroxol, amodiaquine, and its active metabolite (N-monodesethyl amodiaquine) is also discussed. In trying to understand the "hydroxychloroquine" mechanism of action, both pK a and the HCQ aromatic core may play a role. Further, we show that the amodiaquine metabolite and, to a lesser extent, zuclopenthixol and nebivolol are active in a SARS-CoV-2 titer reduction assay. Given the need for improved efficacy and safety, we propose zuclopenthixol, nebivolol, and amodiaquine as potential candidates for clinical trials against the early phase of the SARS-CoV-2 infection and discuss their potential use as adjuvant to the current (i.e., remdesivir and favipiravir) COVID-19 therapeutics.

How to Illuminate the Druggable Genome Using Pharos.

Pharos is an integrated web-based informatics platform for the analysis of data aggregated by the Illuminating the Druggable Genome (IDG) Knowledge Management Center, an NIH Common Fund initiative. The current version of Pharos (as of October 2019) spans 20,244 proteins in the human proteome, 19,880 disease and phenotype associations, and 226,829 ChEMBL compounds. This resource not only collates and analyzes data from over 60 high-quality resources to generate these types, but also uses text indexing to find less apparent connections between targets, and has recently begun to collaborate with institutions that generate data and resources. Proteins are ranked according to a knowledge-based classification system, which can help researchers to identify less studied "dark" targets that could be potentially further illuminated. This is an important process for both drug discovery and target validation, as more knowledge can accelerate target identification, and previously understudied proteins can serve as novel targets in drug discovery. Two basic protocols illustrate the levels of detail available for targets and several methods of finding targets of interest. An Alternate Protocol illustrates the difference in available knowledge between less and more studied targets. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Search for a target and view details Alternate Protocol: Search for dark target and view details Basic Protocol 2: Filter a target list to get refined results.

A Selective Ligand for Estrogen Receptor Proteins Discriminates Rapid and Genomic Signaling.

Estrogen exerts extensive and diverse effects throughout the body of women. In addition to the classical nuclear estrogen receptors (ERα and ERß), the G protein-coupled estrogen receptor GPER is an important mediator of estrogen action. Existing ER-targeted therapeutic agents act as GPER agonists. Here, we report the identification of a small molecule, named AB-1, with the previously unidentified activity of high selectivity for binding classical ERs over GPER. AB-1 also possesses a unique functional activity profile as an agonist of transcriptional activity but an antagonist of rapid signaling through ERα. Our results define a class of small molecules that discriminate between the classical ERs and GPER, as well as between modes of signaling within the classical ERs. Such an activity profile, if developed into an ER antagonist, could represent an opportunity for the development of first-in-class nuclear hormone receptor-targeted therapeutics for breast cancer exhibiting reduced acquired and de novo resistance.

How to Prepare a Compound Collection Prior to Virtual Screening.

Virtual screening is a well-established technique that has proven to be successful in the identification of novel biologically active molecules, including drug repurposing. Whether for ligand-based or for structure-based virtual screening, a chemical collection needs to be properly processed prior to in silico evaluation. Here we describe our step-by-step procedure for handling very large collections (up to billions) of compounds prior to virtual screening.

DrugCentral 2018: an update.

DrugCentral is a drug information resource (http://drugcentral.org) open to the public since 2016 and previously described in the 2017 Nucleic Acids Research Database issue. Since the 2016 release, 103 new approved drugs were updated. The following new data sources have been included: Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), FDA Orange Book information, L1000 gene perturbation profile distance/similarity matrices and estimated protonation constants. New and existing entries have been updated with the latest information from scientific literature, drug labels and external databases. The web interface has been updated to display and query new data. The full database dump and data files are available for download from the DrugCentral website.

Activation of Rho Family GTPases by Small Molecules.

Ras and Ras-related small GTPases are key regulators of diverse cellular functions that impact cell growth, survival, motility, morphogenesis, and differentiation. They are important targets for studies of disease mechanisms as well as drug discovery. Here, we report the characterization of small molecule agonists of one or more of six Rho, Rab, and Ras family GTPases that were first identified through flow cytometry-based, multiplexed high-throughput screening of 200000 compounds. The activators were categorized into three distinct chemical families that are represented by three lead compounds having the highest activity. Virtual screening predicted additional compounds with potential GTPase activating properties. Secondary dose-response assays performed on compounds identified through these screens confirmed agonist activity of 43 compounds. While the lead and second most active small molecules acted as pan activators of multiple GTPase subfamilies, others showed partial selectivity for Ras and Rab proteins. The compounds did not stimulate nucleotide exchange by guanine nucleotide exchange factors and did not protect against GAP-stimulated GTP hydrolysis. The activating properties were caused by a reversible stabilization of the GTP-bound state and prolonged effector protein interactions. Notably, these compounds were active both in vitro and in cell-based assays, and small molecule-mediated changes in Rho GTPase activities were directly coupled to measurable changes in cytoskeletal rearrangements that dictate cell morphology.

Unexplored therapeutic opportunities in the human genome.

This corrects the article DOI: 10.1038/nrd.2018.14.

Unexplored therapeutic opportunities in the human genome.

A large proportion of biomedical research and the development of therapeutics is focused on a small fraction of the human genome. In a strategic effort to map the knowledge gaps around proteins encoded by the human genome and to promote the exploration of currently understudied, but potentially druggable, proteins, the US National Institutes of Health launched the Illuminating the Druggable Genome (IDG) initiative in 2014. In this article, we discuss how the systematic collection and processing of a wide array of genomic, proteomic, chemical and disease-related resource data by the IDG Knowledge Management Center have enabled the development of evidence-based criteria for tracking the target development level (TDL) of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. We then present spotlights on the TDL categories as well as key drug target classes, including G protein-coupled receptors, protein kinases and ion channels, which illustrate the nature of the unexplored opportunities for biomedical research and therapeutic development.