NRIP3 Human

What is NRIP3 and what are its fundamental molecular characteristics?

NRIP3 (Nuclear Receptor Interacting Protein 3) is a protein-coding gene that produces a transcript of 567 nucleotides in length with cytosolic subcellular localization . The protein functions as an interactor with nuclear receptors and demonstrates context-dependent regulatory roles in cellular processes. NRIP3 protein can be detected in both nuclear and cytoplasmic compartments, suggesting potential shuttling between these cellular locations .

The functional impact of NRIP3 varies significantly between cancer types, with evidence suggesting opposing roles in different tissues. For example, in esophageal squamous cell carcinoma (ESCC), NRIP3 appears to promote tumor growth and therapy resistance , while in colorectal cancer (CRC), it exhibits tumor-suppressive properties by inhibiting cell proliferation, colony formation, invasion, and migration .

How is NRIP3 expression regulated in human tissues?

NRIP3 expression is primarily regulated through epigenetic mechanisms, particularly DNA methylation of its promoter region. Research demonstrates an inverse correlation between NRIP3 expression and promoter methylation status. In colorectal cancer studies, immunohistochemistry assays reveal higher NRIP3 expression in normal margin tissue compared to cancer tissues (p < 0.001), with reduced expression significantly associated with promoter methylation (p < 0.001) .

The methylation pattern of NRIP3 shows progressive changes during cancer development, with methylation observed in 2.7% of resected margin samples, 32.2% of colorectal adenomatous polyps, and 50.6% of colorectal cancer samples . This progressive increase suggests that NRIP3 methylation may represent an early event in carcinogenesis.

In stress response studies, NRIP3 shows variable methylation patterns (hypomethylation and mixed methylation) in response to different stressors, indicating another layer of epigenetic regulation in non-cancer contexts .

What signaling pathways does NRIP3 interact with or influence?

NRIP3 interacts with several critical cellular signaling pathways:

• PI3K-AKT Signaling: In colorectal cancer, NRIP3 has been demonstrated to suppress the PI3K-AKT pathway. Microarray analysis and subsequent validation showed that reexpression of NRIP3 in CRC cell lines (DLD1, RKO, and HCT116) reduced levels of PI3K, phosphorylated AKT (p-AKT), and phosphorylated mTOR (p-mTOR), while knockdown of NRIP3 in DKO cells increased these signaling molecules .

• PPARα-Mediated Signaling: In esophageal squamous cell carcinoma, NRIP3 increases DDI1 expression via PPARα, establishing a NRIP3-PPARα-DDI1-RTF2 axis that mediates resistance to chemoradiotherapy .

• DNA Damage Response: NRIP3 has been implicated in replication stress management through its interaction with RTF2 (homologous to Schizosaccharomyces pombe Rtf2), which is involved in cellular responses to DNA damage induced by chemoradiotherapy .

• Matrix Metalloproteinase Regulation: In functional studies, NRIP3 expression has been shown to affect levels of MMP2, MMP7, and MMP9, which are involved in extracellular matrix remodeling and cancer cell invasion .

What techniques are most effective for investigating NRIP3 methylation?

Researching NRIP3 methylation requires a multi-modal approach to capture both site-specific and global methylation patterns:

• Methylation-Specific PCR (MS-PCR): This technique has been effectively employed in multiple studies to analyze the methylation status of the NRIP3 promoter region. In colorectal cancer research, MS-PCR successfully detected NRIP3 methylation in various sample types including resected margins, adenomatous polyps, and cancer tissues .

• Bisulfite Sequencing: For more comprehensive analysis of CpG islands within the NRIP3 promoter, bisulfite sequencing provides base-pair resolution of methylation status. This approach can identify specific CpG sites that may be most critical for expression regulation.

• Whole-Genome Methylation Arrays: Technologies such as the Illumina Infinium arrays can assess genome-wide methylation patterns, providing context for NRIP3 methylation within the broader epigenetic landscape.

• Combined Approaches: When investigating NRIP3 methylation in relation to stress responses, researchers have employed combined approaches to evaluate both global and gene-specific methylation changes. This includes evaluation of 5-hydroxymethylcytosine (5-hmC) modifications, which represent an intermediate in the demethylation process .

When designing methylation studies, researchers should carefully consider cell type specificity, as methylation patterns can vary significantly across tissues. Additionally, correlation of methylation data with expression analysis (RNA and protein levels) strengthens the functional interpretation of methylation changes.

What are the recommended approaches for investigating NRIP3's functional role in cancer cells?

To comprehensively characterize NRIP3's function in cancer cells, researchers should employ a multi-faceted experimental strategy:

• Expression Modulation:

  • RNA interference (siRNA) for NRIP3 knockdown in cells with high endogenous expression

  • Overexpression vectors for reintroduction in cells with low expression or methylated NRIP3

  • CRISPR-Cas9 for complete knockout studies

  • Inducible expression systems for temporal control

• Phenotypic Assays:

  • Proliferation assays (MTT, BrdU incorporation)

  • Colony formation assays to assess clonogenic potential

  • Cell cycle analysis using flow cytometry (particularly for G1/S transition given NRIP3's role in cell cycle arrest)

  • Transwell migration and invasion assays

  • Scratch/wound healing assays for cell migration

• Molecular Pathway Analysis:

  • Western blotting to assess signaling pathway components (PI3K, AKT, mTOR)

  • Co-immunoprecipitation to identify protein-protein interactions

  • Gene expression profiling (RNA-seq or microarray) following NRIP3 modulation

  • Chromatin immunoprecipitation to identify potential DNA binding sites

• In Vivo Models:

  • Xenograft models using cells with modified NRIP3 expression

  • Metastasis models to assess NRIP3's impact on cancer spread

This methodological framework has successfully revealed NRIP3's role in colorectal cancer, where it was shown to suppress migration and invasion. In NRIP3-silenced versus NRIP3-expressing DLD1, RKO, and HCT116 cells, significant differences were observed in migratory cell counts (224.00 ± 13.74 vs 178.08 ± 7.97, 176.92 ± 6.69 vs 102.5 ± 9.71, and 232.63 ± 11.55 vs 181.40 ± 18.65, respectively) .

What are the challenges and solutions in detecting NRIP3 protein in clinical samples?

Detecting NRIP3 protein in clinical samples presents several technical challenges that researchers should address through careful methodological design:

• Antibody Specificity and Validation:

  • Challenge: Limited specificity of available antibodies can lead to false positive signals

  • Solution: Validate antibodies using positive and negative controls, including cells with NRIP3 knockdown or overexpression

  • Recommendation: Use multiple antibodies targeting different epitopes to confirm findings

• Subcellular Localization:

  • Challenge: NRIP3 has been detected in both nuclear and cytoplasmic compartments

  • Solution: Employ subcellular fractionation techniques when using western blotting

  • Recommendation: For immunohistochemistry, score nuclear and cytoplasmic staining separately

• Tissue Heterogeneity:

  • Challenge: Variable NRIP3 expression across different cell types within a tissue

  • Solution: Laser capture microdissection to isolate specific cell populations

  • Recommendation: Use serial sections for correlation with cell type-specific markers

• Quantification Methods:

  • Challenge: Establishing consistent scoring systems for immunohistochemistry

  • Solution: Digital pathology with automated scoring algorithms

  • Recommendation: Implement H-score or Allred scoring systems for semi-quantitative assessment

• Sample Preservation:

  • Challenge: Protein degradation in archived samples

  • Solution: Optimize protocols for protein extraction from FFPE tissues

  • Recommendation: When possible, utilize fresh-frozen tissue for more reliable protein detection

These approaches have been successfully implemented in colorectal cancer research, where immunohistochemistry assays demonstrated significant differences in NRIP3 expression between tumor and margin tissues, with correlation to methylation status .

How does NRIP3 function differ between cancer types?

NRIP3 exhibits remarkably distinct functions across different cancer types, highlighting the importance of tissue context in determining its role:

• Esophageal Squamous Cell Carcinoma (ESCC):

  • Oncogenic Function: NRIP3 promotes tumor cell growth

  • Therapy Resistance: Confers resistance to chemoradiotherapy (CRT)

  • Molecular Mechanism: Functions through a NRIP3-PPARα-DDI1-RTF2 axis

  • NRIP3 increases and binds to DDI1 and RTF2, accelerating RTF2 removal

  • Clinical Correlation: Elevated NRIP3 levels associate with poor outcomes in patients receiving radiotherapy and/or cisplatin-based chemotherapy

• Colorectal Cancer (CRC):

  • Tumor-Suppressive Function: Inhibits cell proliferation, colony formation, invasion, and migration

  • Cell Cycle Regulation: Induces G1/S arrest

  • Signaling Pathway: Suppresses tumor growth by inhibiting PI3K-AKT signaling

  • Molecular Evidence: Reexpression of NRIP3 reduces levels of MMP2, MMP7, and MMP9

  • Clinical Correlation: NRIP3 methylation (leading to reduced expression) associates with poor prognosis

  • Multivariate analysis confirms NRIP3 methylation as an independent poor prognostic marker (HR: 2.256, 95% CI: 1.069–4.761, P=0.033)

This functional dichotomy suggests that NRIP3's role is highly context-dependent and likely influenced by tissue-specific interaction partners, signaling networks, and epigenetic landscapes. Researchers must carefully consider this context-dependency when designing studies and interpreting results across different cancer types.

What is the relationship between NRIP3 methylation and cancer progression?

NRIP3 methylation shows a progressive pattern during cancer development and correlates with several clinicopathological features:

This data demonstrates that NRIP3 methylation remains a significant prognostic factor even after adjusting for other clinical variables .

• Therapeutic Implications:

  • Synthetic Lethality: NRIP3 methylation sensitizes colorectal cancer cells to combined PI3K and ATR/ATM inhibitors

  • Potential Biomarker: Could serve for patient stratification in clinical trials of targeted therapies

These findings collectively suggest that NRIP3 methylation is not merely a passenger event but plays a functional role in cancer progression and could serve as a valuable biomarker.

How does NRIP3 modulate response to cancer therapies?

NRIP3 significantly influences therapeutic responses through distinct mechanisms in different cancer types:

• In Esophageal Squamous Cell Carcinoma (ESCC):

  • Therapy Resistance: NRIP3 upregulation confers resistance to chemoradiotherapy (CRT)

  • Molecular Mechanism: NRIP3 promotes resistance through the NRIP3-PPARα-DDI1-RTF2 axis

  • DNA Damage Response: NRIP3 accelerates the removal of RTF2, a key determinant for managing replication stress

  • Replication Stress Protection: This pathway represents a protective mechanism against DNA damage induced by chemoradiotherapy

  • Clinical Impact: Elevated NRIP3 correlates with poor outcomes in patients receiving radiotherapy and/or cisplatin-based chemotherapy

• In Colorectal Cancer (CRC):

  • Synthetic Lethality: NRIP3 methylation (which reduces expression) sensitizes cells to combined PI3K and ATR/ATM inhibitors

  • Signaling Pathway Involvement: NRIP3 suppresses PI3K-AKT signaling, which may influence cellular response to targeted therapies

  • Cell Cycle Effects: NRIP3's role in G1/S arrest may affect sensitivity to cell cycle-targeted therapies

  • Potential Therapeutic Strategy: Restoring NRIP3 expression might enhance therapeutic efficacy in certain contexts

• Stress Response Connection:

  • Epigenetic Stress Response: NRIP3 shows altered methylation patterns in response to various stressors

  • Potential Mechanism: This epigenetic plasticity may contribute to adaptive responses to therapeutic stress

  • Connection to Other Stress-Response Genes: NRIP3 methylation changes may occur alongside modifications to genes like Nr3c1, OXTR, SLC6A4, and BDNF, which are involved in stress response pathways

These findings highlight NRIP3's potential as both a predictive biomarker for therapy response and a therapeutic target for enhancing treatment efficacy. The context-dependent nature of NRIP3's effects emphasizes the need for cancer type-specific assessment when considering its role in therapeutic strategies.

What mechanisms might explain NRIP3's opposing roles in different cancer types?

The contrasting functions of NRIP3 across cancer types suggest several mechanisms that warrant investigation:

• Tissue-Specific Protein Interactions:

  • In ESCC: NRIP3 interacts with DDI1 and RTF2, promoting therapy resistance

  • In CRC: NRIP3 appears to suppress PI3K-AKT signaling through as-yet unidentified interactions

  • Different binding partners in distinct tissue contexts may direct NRIP3 to different functional outcomes

• Signaling Pathway Integration:

  • NRIP3 interacts with the PPARα pathway in ESCC, increasing DDI1 expression

  • In CRC, NRIP3 inhibits PI3K, p-AKT, and p-mTOR levels

  • The integration of NRIP3 into different signaling networks may determine its ultimate effect on cell behavior

• Cell Type-Specific Epigenetic Regulation:

  • Methylation of NRIP3 occurs at different frequencies across cancer types

  • The specific CpG sites methylated may differ, potentially affecting protein function or interactions

  • Differential epigenetic regulation might result in expression of different NRIP3 isoforms

• Subcellular Localization Differences:

  • NRIP3 has been detected in both nuclear and cytoplasmic compartments

  • Different cancer types might exhibit different patterns of NRIP3 localization, affecting its functional interactions

  • Nuclear localization could promote transcriptional regulatory functions while cytoplasmic localization might favor signaling pathway interactions

• Post-Translational Modifications:

  • Cancer type-specific patterns of phosphorylation, ubiquitination, or other modifications could alter NRIP3 function

  • These modifications might affect protein stability, binding partner preferences, or enzymatic activity

Understanding these mechanisms requires integrated approaches combining proteomics, transcriptomics, and functional studies across multiple cancer types using standardized methodologies.

How might NRIP3 be connected to stress response mechanisms?

Evidence suggests potential connections between NRIP3 and cellular stress response pathways:

• Epigenetic Regulation in Stress Conditions:

  • NRIP3 has been identified among genes showing altered methylation patterns (hypomethylation and mixed methylation) in response to various stressors

  • This places NRIP3 within a broader network of epigenetically regulated stress-responsive genes

• Connection to DNA Damage Response:

  • In ESCC, NRIP3 interacts with RTF2, which is involved in managing replication stress

  • This interaction affects cellular responses to DNA damage induced by chemoradiotherapy

  • The NRIP3-PPARα-DDI1-RTF2 axis represents a protective pathway against replication stress

• Potential Relationship to Glucocorticoid Signaling:

  • As a nuclear receptor interacting protein, NRIP3 might modulate the function of stress-related nuclear receptors

  • Studies have identified altered methylation in the glucocorticoid receptor gene (Nr3c1) in response to stress

  • NRIP3 might function within this broader network of stress-responsive epigenetic regulation

• Association with Other Stress-Response Genes:

  • NRIP3 methylation changes appear alongside modifications to genes like Nr3c1, OXTR, SLC6A4, and BDNF

  • These genes are involved in neuronal development, hormonal regulation, and susceptibility to stress-related disorders

  • This suggests NRIP3 may be part of an integrated stress response network

Further investigation into NRIP3's role in stress responses could reveal new insights into how cellular stress influences cancer development and therapy response, potentially identifying novel intervention points for cancer treatment.

What is the potential of NRIP3 as a prognostic or predictive biomarker?

NRIP3 shows considerable promise as both a prognostic and predictive biomarker across different cancer types:

• Prognostic Value in Colorectal Cancer:

  • NRIP3 methylation independently predicts poor prognosis (HR: 2.256, 95% CI: 1.069–4.761, P=0.033)

  • Associates with clinicopathological features including late onset, poor differentiation, and lymph node metastasis

  • The progressive increase in methylation frequency from normal tissue (2.7%) to adenomas (32.2%) to cancer (50.6%) suggests utility as an early detection marker

• Predictive Value for Therapy Response:

  • In ESCC: Elevated NRIP3 predicts poor response to chemoradiotherapy

  • In CRC: NRIP3 methylation may predict sensitivity to combined PI3K and ATR/ATM inhibitors

  • This context-dependent predictive value requires cancer type-specific assessment and validation

• Clinical Implementation Considerations:

  • Methylation-specific PCR provides a practical method for clinical testing

  • NRIP3 methylation assessment could be integrated into existing molecular testing panels

  • Immunohistochemistry for NRIP3 protein offers a complementary approach accessible to most pathology laboratories

• Potential in Liquid Biopsy:

  • DNA methylation markers can often be detected in circulating cell-free DNA

  • NRIP3 methylation might serve as a non-invasive biomarker for monitoring disease progression or treatment response

• Validation Requirements:

  • Large-scale multicenter validation studies with standardized methodologies

  • Prospective clinical trials evaluating NRIP3 status as a stratification factor

  • Establishment of standardized cutoff values for clinical interpretation

The development of NRIP3 as a clinical biomarker would benefit from considering cancer type-specific contexts and potentially combining NRIP3 status with other molecular markers for enhanced prognostic or predictive power.

How should researchers address the tissue-specific nature of NRIP3 function?

The context-dependent role of NRIP3 across different cancer types necessitates specific methodological approaches:

• Comprehensive Tissue Analysis:

  • Systematic evaluation of NRIP3 expression, methylation, and function across multiple tissue types

  • Use of tissue microarrays to efficiently assess multiple samples

  • Inclusion of normal, pre-malignant, and malignant tissue from the same organ to track progressive changes

• Standardized Experimental Systems:

  • Establish a panel of cell lines from different tissue origins for parallel testing

  • Employ identical methodologies across different cancer types to eliminate technical variability

  • Use isogenic cell line pairs differing only in NRIP3 status to isolate its specific effects

• Context-Specific Interaction Analysis:

  • Perform proteomics studies to identify tissue-specific NRIP3 interactors

  • Use proximity ligation assays or BioID approaches to capture interactions in their native cellular context

  • Validate key interactions through co-immunoprecipitation and functional studies

• Pathway-Specific Analyses:

  • Conduct focused pathway analyses (e.g., PI3K-AKT in CRC, PPARα-DDI1-RTF2 in ESCC)

  • Use pathway inhibitors to validate the functional significance of identified interactions

  • Employ reporter assays to quantify pathway activity in response to NRIP3 modulation

• In Vivo Models:

  • Develop tissue-specific transgenic models to study NRIP3 function in different organs

  • Use orthotopic xenograft models to maintain appropriate tissue microenvironment

  • Compare systemic versus tissue-specific effects through careful experimental design

These methodological approaches can help distinguish genuine biological differences from technical artifacts and provide a more coherent understanding of NRIP3's complex, context-dependent biology.

What strategies can resolve contradictory findings about NRIP3 in the literature?

Addressing contradictory findings about NRIP3 requires systematic approaches to distinguish biological variation from methodological differences:

• Meta-Analysis and Systematic Review:

  • Comprehensive review of existing literature with attention to methodological details

  • Statistical meta-analysis where appropriate data exists

  • Identification of patterns in contradictions (e.g., cancer type-specific differences)

• Reproducibility Studies:

  • Direct replication of key experiments using identical methodologies

  • Multi-center collaborative studies with standardized protocols

  • Pre-registration of study designs to reduce reporting bias

• Methodological Standardization:

  • Development of reference materials and standards for NRIP3 detection

  • Validation of antibodies and primers across multiple laboratories

  • Establishment of common cell line models for comparative studies

• Comprehensive Molecular Profiling:

  • Integrate transcriptomic, proteomic, and epigenomic analyses

  • Profile multiple cancer types using identical platforms

  • Identify molecular contexts associated with different NRIP3 functions

• Direct Comparison Studies:

  • Design experiments specifically to test competing hypotheses

  • Include multiple cancer types within the same experimental framework

  • Control for variables that might explain contradictions (genetic background, experimental conditions)

• Isoform-Specific Analysis:

  • Identify and characterize potential NRIP3 isoforms

  • Develop isoform-specific detection methods

  • Test whether different isoforms explain contradictory functional observations

These approaches can help resolve contradictions and develop a more unified understanding of NRIP3's biology that accommodates legitimate context-dependent variations in function.

What are the best practices for translating NRIP3 research into clinical applications?

Translating NRIP3 research into clinical applications requires addressing several challenges:

• Biomarker Development:

  • Analytical Validation:

    • Establish reproducible, standardized assays for NRIP3 methylation and expression

    • Determine analytical sensitivity, specificity, and reproducibility

    • Validate across multiple laboratories and platforms

  • Clinical Validation:

    • Conduct large-scale studies correlating NRIP3 status with clinical outcomes

    • Establish clinically meaningful cutoff values

    • Validate in prospective clinical trials

• Therapeutic Target Development:

  • Target Validation:

    • Confirm NRIP3's role in appropriate disease models

    • Identify patient populations most likely to benefit from NRIP3-targeted therapies

    • Develop pharmacodynamic biomarkers to confirm target engagement

  • Context-Specific Approaches:

    • Design inhibition strategies for contexts where NRIP3 promotes disease (e.g., ESCC)

    • Develop approaches to restore NRIP3 function where it acts as a tumor suppressor (e.g., CRC)

    • Consider combination strategies targeting NRIP3-related pathways

• Clinical Trial Design:

  • Biomarker-Guided Patient Selection:

    • Stratify patients based on NRIP3 status (expression or methylation)

    • Consider cancer type-specific enrollment criteria

    • Include companion diagnostic development

  • Appropriate Endpoints:

    • Select endpoints relevant to NRIP3's biological effects

    • Consider intermediate biomarker endpoints (e.g., pathway activation)

    • Design trials with sufficient statistical power for biomarker-defined subgroups

• Regulatory Considerations:

  • Companion Diagnostic Development:

    • Coordinate therapeutic and diagnostic development

    • Address regulatory requirements for biomarker validation

    • Ensure analytical performance meets clinical needs

  • Evidence Generation:

    • Design pivotal studies to meet regulatory standards

    • Consider accelerated approval pathways where appropriate

    • Plan post-approval studies to address remaining questions

These best practices can help facilitate the translation of NRIP3 research into clinical applications that meaningfully impact patient care.

What are the most promising future directions for NRIP3 research?

NRIP3 research holds significant promise in several key areas that warrant further investigation:

• Mechanistic Understanding:

  • Elucidation of the molecular mechanisms underlying NRIP3's context-dependent functions in different cancer types

  • Identification of tissue-specific interaction partners and regulatory networks

  • Characterization of potential NRIP3 isoforms and their functional significance

• Epigenetic Regulation:

  • Detailed mapping of the regulatory elements controlling NRIP3 expression

  • Investigation of dynamic changes in NRIP3 methylation during disease progression

  • Exploration of potential epigenetic therapies to modulate NRIP3 expression in disease contexts

• Clinical Applications:

  • Development and validation of NRIP3 as a prognostic biomarker in colorectal cancer

  • Evaluation of NRIP3 as a predictive biomarker for targeted therapy response

  • Investigation of NRIP3 status in non-invasive liquid biopsy approaches

• Therapeutic Targeting:

  • Development of strategies to inhibit NRIP3 in contexts where it promotes disease

  • Exploration of approaches to restore NRIP3 function where it acts as a tumor suppressor

  • Investigation of synthetic lethal interactions, particularly in NRIP3-methylated cancers

• Broader Disease Relevance:

  • Extension of NRIP3 research beyond the currently studied cancer types

  • Investigation of NRIP3's role in non-cancer diseases, particularly stress-related disorders

  • Exploration of potential germline variations affecting NRIP3 function

Advancing these research directions will require multidisciplinary approaches combining molecular biology, epigenetics, clinical oncology, and computational biology to fully understand and leverage NRIP3's complex biology for improved patient care.

What methodological innovations would accelerate NRIP3 research?

Several methodological innovations could significantly advance NRIP3 research:

• Advanced Genomic Technologies:

  • CRISPR-based epigenome editing to precisely modify NRIP3 methylation status

  • Single-cell multi-omics to characterize NRIP3 regulation and function at cellular resolution

  • Spatial transcriptomics and proteomics to map NRIP3 expression patterns within tissue contexts

• Protein Structure and Interaction Analysis:

  • Cryo-EM or X-ray crystallography of NRIP3 protein complexes

  • Hydrogen-deuterium exchange mass spectrometry to map dynamic protein interactions

  • Proximity labeling approaches (BioID, APEX) to identify context-specific interactors

• In Vivo Models:

  • Development of conditional knockout/knockin models with tissue-specific NRIP3 modulation

  • Patient-derived organoids to study NRIP3 function in near-native contexts

  • Humanized mouse models to better recapitulate human-specific aspects of NRIP3 biology

• Computational Approaches:

  • Systems biology models integrating multi-omics data to predict NRIP3 function

  • Machine learning approaches to identify patterns in NRIP3 regulation across cancer types

  • Network analysis to contextualize NRIP3 within broader cellular processes

• Translational Tools:

  • Development of standardized assays for clinical assessment of NRIP3 status

  • Digital pathology approaches for automated quantification of NRIP3 in tissue samples

  • Liquid biopsy methods to detect NRIP3 methylation in circulating DNA

These methodological innovations would enable more comprehensive, precise, and clinically relevant characterization of NRIP3, accelerating both basic understanding and translational applications.