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Integrated multi-omics analyses identify an RAS-SLC11A2-associated molecular framework linking iron metabolism with PCOS-related cardiometabolic risk.

INTRODUCTION: PCOS is a common endocrine disorder with elevated cardiometabolic risk, yet the role of the renin-angiotensin system (RAS)-iron metabolism axis in this comorbidity remains unclear. We explored its underlying mechanisms and evaluated the therapeutic potential of gentiopicroside. METHODS: Integrated multi-omics analyses combining transcriptomics, single-cell RNA sequencing, Mendelian randomization, machine learning, molecular docking, and in vitro functional assays were performed to identify shared molecular pathways and therapeutic targets across PCOS, hypertension, NAFLD, and T2DM. RESULTS: SLC11A2 was consistently dysregulated in PCOS transcriptomic datasets, and associated with iron metabolism, inflammatory response and oxidative stress pathways. Genetic analyses validated RAS-related regulation in hypertension susceptibility and revealed shared genetic architecture between PCOS and cardiometabolic traits. Network and single-cell analyses characterized SLC11A2-associated molecular patterns in disease-relevant cell types; machine learning identified disease-classifying molecular signatures. Gentiopicroside alleviated inflammatory and oxidative stress phenotypes, including reduced IL-6 expression and reactive oxygen species accumulation. CONCLUSION: This study defines an RAS-SLC11A2 molecular framework linking iron metabolism dysregulation to PCOS-related cardiometabolic risk, elucidating the mechanisms connecting ovarian dysfunction, inflammation, oxidative stress and hypertension, and supports gentiopicroside as a promising therapeutic candidate.

Humans↗

What do -omics mean for the science and policy of the nutritional sciences?

The development of systems biology is revolutionizing the way we are studying and learning about human health. It is a way of thinking and a systematic attempt to integrate information from several fields of study (physical, biological, chemical, engineering, etc) to develop a more kinetic and real-time understanding of complex biological processes. It uses mathematical modeling tools to chart dynamic interactions between the components of a biological system, eg, genes, transcripts, proteins, metabolites, and cells, to simulate and analyze networks and pathways and the spatial and temporal relations that exist in biological systems. The term -omics represents the rigorous study of various collections of molecules, biological processes, or physiologic functions and structures as systems, represented most prominently by genomics. In the field of nutrition, had a systems approach been applied to evaluating the effect of vitamin A status on mortality rates in young children in developing countries, it might not have taken 20 y to go from the initial epidemiologic observations to global vitamin A supplementation programs. Better understanding of the functional biology of retinoids on different tissues that mediate host resistance to infection, and their synergistic interactions in biological, metabolic, and functional terms, could have provided a plausible mechanism for the observed effect on mortality. There are 3 policy take-home messages: 1) When controversies exist, invest in the science needed to sort them out. 2) Increase the amounts of money available for health research and interventions relevant to developing countries. 3) Ensure that policymakers understand the issues and why they are important and understand the science and its relevance.

Animals↗

Combining different 'omics' technologies to map and validate protein-protein interactions in humans.

The mapping of protein-protein interactions is key to understanding biological processes. Many technologies have been reported to map interactions and these have been systematically applied in yeast. To date, the number of reported yeast protein interactions that have been truly validated by at least one other approach is low. The mapping of human protein interaction networks is even more complicated. Thus, it is unreasonable to try to map the human interactome; instead, interaction mapping in human cell lines should be focused along the lines of diseases or changes that can be associated with specific cells. In this paper, an approach for combining different 'omics' technologies to achieve efficient mapping and validation of protein interactions in human cell lines is presented.

Cell Line↗

MNMO: discover driver genes from a multi-omics data based-multi-layer network.

MOTIVATION: Cancer as a public health problem is driven by genomic variations in "cancer driver" genes. The identification of driver genes is critical for the discovery of key biomarkers and the development of personalized therapy. RESULTS: We propose a prediction method MNMO: a multi-layer network model based on multi-omics data. MNMO firstly constructs a dynamically adjusted four-layer network composed of miRNAs and three kinds of genes with different features. Then three kinds of scores, i.e. control capacity, mutation score, and network score, are devised and calculated by harmonic mean to produce the integrated gene score. Experiments were performed on three kinds of real cancer data to compare the identification performance of method MNMO with that of six state-of-the-art ones. The results indicate that method MNMO presents the best identification performance under most circumstances. The genes prioritized by method MNMO not only have a better match to the benchmark ones than those identified by the other methods, but also are all associated with the development and progression of cancers. In addition, some extended versions of method MNMO can further achieve better performance on most evaluation metrics for some specific datasets. They may be more conducive to identifying tissue-specific genes, which has been verified through a number of experiments. AVAILABILITY AND IMPLEMENTATION: The source code and the R package "MNMO" are available at https://github.com/Zheng-D/MNMO. The dataset and code are archived at https://doi.org/10.5281/zenodo.14969986.

Humans↗

Integration of multi-source gene interaction networks and omics data with graph attention networks to identify novel disease genes.

MOTIVATION: The pathogenesis of diseases is closely associated with genes, and the discovery of disease genes holds significant importance for understanding disease mechanisms and designing targeted therapeutics. However, biological validation of all genes for diseases is expensive and challenging. RESULTS: In this study, we propose DGP-AMIO, a computational method based on graph attention networks, to rank all unknown genes and identify potential novel disease genes by integrating multi-omics and gene interaction networks from multiple data sources. DGP-AMIO outperforms other methods significantly on 20 disease datasets, with an average AUROC and AUPR exceeding 0.9. The superior performance of DGP-AMIO is attributed to the integration of multiomics and gene interaction networks from multiple databases, as well as triGAT, a proposed GAT-based method that enables precise identification of disease genes in directed gene networks. Enrichment analysis conducted on the top 100 genes predicted by DGP-AMIO and literature research revealed that a majority of enriched GO terms, KEGG pathways and top genes were associated with diseases supported by relevant studies. We believe that our method can serve as an effective tool for identifying disease genes and guiding subsequent experimental validation efforts. AVAILABILITY AND IMPLEMENTATION: DGP-AMIO is publicly available at https://github.com/yangkaiyuan1027/DGP-AMIO.

Gene Regulatory Networks↗

Composition-on-composition regression analysis for multi-omics integration of metagenomic data.

MOTIVATION: Compositional data are frequently encountered in many disciplines, such as in next-generation sequencing experiments widely used in biomedical studies. Regression analysis with compositional data as either responses or predictors has been well studied. However, when both responses and predictors are compositional, the inventory of analysis tools is surprisingly limited, especially in the high-dimensional setting. Among the few existing methods, most of them rely on a log-ratio transformation to move compositional data from the simplex to real numbers. Yet, a serious weakness of these methods is their failure to handle the substantial fraction of zeroes observed in data collected from next-generation sequencing experiments. RESULTS: To investigate associations between two high-dimensional multi-omics compositions, we propose a composition-on-composition (COC) regression analysis method which does not require log-ratio transformations and hence can handle zeroes in the data. To account for high dimensionality, we estimate regression coefficients using a penalized estimation equation approach. Finally, inference procedures for COC regression are also proposed. Superior performance of COC is demonstrated through both comprehensive numerical simulations and case studies. AVAILABILITY AND IMPLEMENTATION: Source R codes to implement COC method is available at https://github.com/nrios4/COC.

Regression Analysis↗

phylobar: an R package for multiresolution compositional barplots in omics studies.

SUMMARY: Stacked barplots, though widely used in microbiome studies, can obscure important patterns in microbiome data. They omit rare taxa and can mask shifts that emerge at finer taxonomic levels. To address this issue, we introduce phylobar, an R package that interactively links stacked barplots with overview phylogenetic or taxonomic hierarchies. The interface allows users to collapse or expand subtrees, paint color palettes interactively, and search for specific taxa. This allows comparison across taxonomic resolutions that are hidden in static overviews. phylobar works with any omics data with hierarchical organization, including cell type hierarchies, as we demonstrate in a case study of immune cell composition in COVID-19 patients. AVAILABILITY AND IMPLEMENTATION: phylobar is available as an R package on GitHub. It uses the htmlwidgets library to link interactive D3 visualizations with R. The interactive plots can be embedded within R Markdown or Quarto notebooks, and views can be exported as vector graphics files. The package is open source and documented at https://mkdiro-O.github.io/phylobar.

Software↗

EMTscore infers divergent EMT pathways from omics data and enables rapid screening for EMT-associated gene sets.

MOTIVATION: Quantitative analyses of epithelial-mesenchymal transition (EMT) have been widely used in several areas of biomedical sciences due to its importance in development and cancer progression, but its multi-contextual nature requires standardization and implementation of gene set scoring methods beyond capacities of conventional tools. RESULTS: We developed EMTscore, a package that provides an efficient implementation of unbiased scoring methods for multiple EMT pathways using individual single-cell or bulk omics data, and the package allows rapid screening for cellular processes correlated with EMT. AVAILABILITY AND IMPLEMENTATION: EMTscore is available from GitHub https://github.com/wenmm/EMTscore under the GNU General Public License, and is uploaded on Zenodo with a DOI 10.5281/zenodo.19487376.

Epithelial-Mesenchymal Transition↗

Integrated multi-omics strategies for identifying novel therapies in psoriasis.

MOTIVATION: Psoriasis is a chronic, immune-mediated disorder with an unmet need for effective treatments. To systematically prioritize therapeutic targets, we integrated proteome-wide Mendelian randomization (MR) with expression validation in blood/skin, genetic susceptibility analysis, differential gene expression (DGE) from bulk and single-cell RNA sequencing (scRNA-seq), colocalization, pathway enrichment, and protein-protein interaction analyses. RESULTS: Proteome-wide MR identified 29 candidate protein targets (Bonferroni-corrected), all replicated in independent datasets. Fifteen targets showed significant expression associations in blood or skin. Eleven proteins-UBLCP1, IL23A, ASF1A, RARRES2, ICAM1, PRSS53, ICAM5, GCA, IL2RA, DBI, and NFKB1-exhibited consistent directional effects with their genes. Genetic susceptibility analysis confirmed 20 target-specific polygenic scores for psoriasis and five for psoriatic arthritis. DGE analysis identified 13 targets in bulk and 13 in scRNA-seq-primarily in keratinocytes and immune cells-with IL2RA, COMP, and A2ML1 dysregulated across both. Colocalization analysis implicated shared causal variants for psoriasis in ASF1A, CD8A, CTF1, IL7R, MMP12, RARRES2, XCL2, DBI, IL23A, IL2RA, SGSH, and TIMD4. Enrichment analyses highlighted involvement in cytotoxicity, immune regulation, and JAK-STAT signaling. Eighteen targets interacted with approved anti-psoriasis drugs. Notably, drugs targeting IL2RA, IL7R, CTF1, ICAM1, MMP12, NFKB1, CD8A, DDX58, IL12A, SGSH, and FAP are approved or in trials for other diseases, suggesting repurposing potential. Our integrative multi-omics approach prioritized 29 high-confidence targets, including 13 novel candidates (RARRES2, ASF1A, CTF1, DBI, B3GNT2, CD8A, TIMD4, CRTAM, SGSH, XCL2, DAPK2, A2ML1, and FAP). Several high-priority targets-such as IL2RA, IL23, MMP12, RARRES2, IL7R, and ICAM1-were supported across analytical layers. These findings provide a robust foundation for psoriasis drug development. AVAILABILITY AND IMPLEMENTATION: The code used for the analyses in this manuscript has been archived in Zenodo at [DOI: 10.5281/zenodo.19692128].

Psoriasis↗

SeqUIaSCOPE: multi-omics data integration platform for single-patient clinical oncology pathway exploration.

SUMMARY: SeqUIaSCOPE is an open-source platform designed for routine clinical oncology diagnostics through case-centric integration and visualization of genomic variants, fusion events, and expression profiles. The platform combines molecular-level validation via embedded genome browsing with systems-level interpretation through dynamic pathway visualization, enabling geneticists to assess how alterations converge across biological networks. Flexible reporting with customizable templates accommodates diverse institutional requirements, while secure cluster-based or local deployment ensures compliance with data protection policies, making advanced multi-omics diagnostics accessible to academic and clinical institutions. AVAILABILITY AND IMPLEMENTATION: SeqUIaSCOPE is freely available on GitHub at https://github.com/BioIT-CEITEC/sequiascope under the MIT license and archived at Zenodo (https://zenodo.org/records/21338445). Due to the sensitive nature of patient data, the repository provides simulated datasets that mimic the structure of real clinical data for testing and exploration. Documentation and a live demo accompany these datasets, allowing users to explore the application without any prior setup. The repository also includes a Helm chart for Kubernetes deployment and Docker containers for local deployment, ensuring compatibility across Linux, macOS, and Windows. No user registration is required, and all data remains on local or institutional infrastructure.

Humans↗

Digital pathology and spatial omics in steatohepatitis: Clinical applications and discovery potentials.

Steatohepatitis with diverse etiologies is the most common histological manifestation in patients with liver disease. However, there are currently no specific histopathological features pathognomonic for metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, or metabolic dysfunction-associated steatotic liver disease with increased alcohol intake. Digitizing traditional pathology slides has created an emerging field of digital pathology, allowing for easier access, storage, sharing, and analysis of whole-slide images. Artificial intelligence (AI) algorithms have been developed for whole-slide images to enhance the accuracy and speed of the histological interpretation of steatohepatitis and are currently employed in biomarker development. Spatial biology is a novel field that enables investigators to map gene and protein expression within a specific region of interest on liver histological sections, examine disease heterogeneity within tissues, and understand the relationship between molecular changes and distinct tissue morphology. Here, we review the utility of digital pathology (using linear and nonlinear microscopy) augmented with AI analysis to improve the accuracy of histological interpretation. We will also discuss the spatial omics landscape with special emphasis on the strengths and limitations of established spatial transcriptomics and proteomics technologies and their application in steatohepatitis. We then highlight the power of multimodal integration of digital pathology augmented by machine learning (ML)algorithms with spatial biology. The review concludes with a discussion of the current gaps in knowledge, the limitations and premises of these tools and technologies, and the areas of future research.

Humans↗

Multi-omic phenotyping of iPSC-derived neurons harboring the MAPT V337M mutation reveals tau hypophosphorylation and perturbed axon morphology pathways.

Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. This is in part due to an incomplete understanding of the normal functions of tau in development and aging, and how the associated molecular and cellular processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation or MAPT knockdown. RNA-seq and phosphoproteomics revealed that both V337M mutation and tau knockdown perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. Functional genomics screens uncovered regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau perturbs tau phosphorylation and axon morphology pathways that are relevant to the normal function of tau, which could contribute to previously reported cognitive changes in preclinical MAPT variant carriers.

Journal Article↗

Integration of Imaging-based and Sequencing-based Spatial Omics Mapping on the Same Tissue Section via DBiTplus.

Spatially mapping the transcriptome and proteome in the same tissue section can significantly advance our understanding of heterogeneous cellular processes and connect cell type to function. Here, we present Deterministic Barcoding in Tissue sequencing plus (DBiTplus), an integrative multi-modality spatial omics approach that combines sequencing-based spatial transcriptomics and image-based spatial protein profiling on the same tissue section to enable both single-cell resolution cell typing and genome-scale interrogation of biological pathways. DBiTplus begins with in situ reverse transcription for cDNA synthesis, microfluidic delivery of DNA oligos for spatial barcoding, retrieval of barcoded cDNA using RNaseH, an enzyme that selectively degrades RNA in an RNA-DNA hybrid, preserving the intact tissue section for high-plex protein imaging with CODEX. We developed computational pipelines to register data from two distinct modalities. Performing both DBiT-seq and CODEX on the same tissue slide enables accurate cell typing in each spatial transcriptome spot and subsequently image-guided decomposition to generate single-cell resolved spatial transcriptome atlases. DBiTplus was applied to mouse embryos with limited protein markers but still demonstrated excellent integration for single-cell transcriptome decomposition, to normal human lymph nodes with high-plex protein profiling to yield a single-cell spatial transcriptome map, and to human lymphoma FFPE tissue to explore the mechanisms of lymphomagenesis and progression. DBiTplusCODEX is a unified workflow including integrative experimental procedure and computational innovation for spatially resolved single-cell atlasing and exploration of biological pathways cell-by-cell at genome-scale.

Journal Article↗

Soluble Immune Checkpoint Protein and Lipid Network Associations with All-Cause Mortality Risk: Trans-Omics for Precision Medicine (TOPMed) Program.

Adverse cardiovascular events are emerging with the use of immune checkpoint therapies in oncology. Using datasets in the Trans-Omics for Precision Medicine program (Multi-Ethnic Study of Atherosclerosis, Jackson Heart Study [JHS], and Framingham Heart Study), we examined the association of immune checkpoint plasma proteins with each other, their associated protein network with high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), and the association of HDL-C- and LDL-C-associated protein networks with all-cause mortality risk. Plasma levels of LAG3 and HAVCR2 showed statistically significant associations with mortality risk. Colocalization analysis using genome wide-association studies of HDL-C or LDL-C and protein quantitative trait loci from JHS and the Atherosclerosis Risk in Communities identified TFF3 rs60467699 and CD36 rs3211938 variants as significantly colocalized with HDL-C; in contrast, none colocalized with LDL-C. The measurement of plasma LAG3, HAVCR2, and associated proteins plus targeted genotyping may identify patients at increased mortality risk.

Journal Article↗

Integrative Multi-Omics Analysis Identifies Thrombosis-Associated Molecular Features Linked to Germline Susceptibility and Immune Cell Communication in Gastric Cancer.

Emerging evidence indicates that coagulation-related molecular programs are associated with thrombosis, tumor progression, and molecular dysregulation in gastric cancer (GC). However, thrombosis-associated molecular features in GC and their potential links to inherited susceptibility remain insufficiently understood. Integrated analyses of transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were performed to identify thrombosis-associated genes and establish a machine learning-based prognostic signature. Genome-wide association study (GWAS), expression quantitative trait loci (eQTL), transcriptome-wide association study (TWAS), and Mendelian randomization (MR) analyses were conducted to investigate susceptibility-associated transcriptional programs in GC. Functional assays were used to evaluate candidate genes associated with malignant phenotypes. Single-cell RNA sequencing (scRNA-seq) and cell-cell communication analyses were further performed to characterize cell-type-specific expression patterns and potential intercellular interactions. A total of 22 differentially expressed thrombosis-associated genes were identified, and a prognostic signature comprising 14 genes was established. The signature stratified patients into high- and low-risk groups and showed prognostic performance in both the training and validation cohorts. Integrative GWAS, eQTL, and TWAS analyses identified susceptibility-associated transcriptional programs that were positively correlated with the thrombosis-associated risk score. Silencing ACTN2 and CRYAB significantly reduced GC cell migration and invasion. scRNA-seq analysis revealed relatively high CRYAB expression in neutrophils, and CellChat analysis suggested potential neutrophil-B cell interactions involving COLLAGEN-related signaling. This integrative multi-omics study identified a thrombosis-associated molecular signature linked to prognosis and germline susceptibility-associated transcriptional programs in GC. ACTN2 and CRYAB may represent candidate genes associated with GC cell migration and invasion, while single-cell analysis suggested potential immune-related communication features.

Humans↗

Beyond parental lines: multi-omics analyses reveal epigenetic and transcriptional mechanisms underlying heterosis in Oryza sativa × Oryza rufipogon hybrids.

Heterosis, or hybrid vigor, refers to the superior phenotypes of a hybrid compared with their parents and is widely exploited in agriculture. Interspecific hybrids within the Oryza genus demonstrate significant potential for the systematic improvement of rice varieties. Nevertheless, the mechanistic basis underlying heterosis in interspecific Oryza hybrids remains poorly understood. Here, we systematically performed phenotypic characterization, whole-genome bisulfite sequencing, RNA sequencing, and small RNA profiling using Oryza sativa L. ssp. japonica cv. Nipponbare (NIP), Oryza rufipogon Griff. acc. CWR, and their resulting F1 hybrid (named as NC). NIP and CWR showed distinct phenotypic and molecular differences. The interspecific hybrid, NC, exhibited significant yield heterosis. In the hybrid, most epigenetic and transcriptional features displayed additive inheritance patterns relative to parental lines. Analysis revealed that domestication-selected genes maintained relatively low DNA methylation coupled with high expression levels in both hybrid and parental lines. Additionally, we identified that non-additive miRNAs were potentially involved in regulating fertility, cell growth, and cell division processes in the hybrid. A significant negative correlation was observed between DNA methylation level and gene expression. Functional enrichment analysis revealed that hybrid-MPV DEGs were significantly associated with flowering time regulation, carbohydrate metabolism, photosynthesis, protein phosphorylation, seed development, and defense responses. Through weighted gene co-expression network analysis, we identified 102 functional gene modules, six of which were significantly associated with yield-related heterosis. Collectively, our results provide a multi-omics framework for understanding interspecific hybridization between elite cultivars and wild rice relatives, highlighting CWR as an untapped genetic reservoir for rice improvement.

Oryza↗

Multi-Omics insights into OsZFP252-OsGA20ox5 mediated drought tolerance in rice through stomatal and vascular regulation.

Rice growth is highly dependent on water availability, and drought stress significantly impacts its entire life cycle. However, previous studies lack systematic investigations into drought-responsive candidate genes across the full life cycle of rice. This study integrates transcriptomic and phenotypic data from two rice lines, IR64 (drought-sensitive) and DK151 (drought-tolerant), under varied environmental conditions at distinct growth stages. Using k-means clustering, 13 369 genes were categorized into 17 distinct expression patterns, revealing drought-responsive genes specifically upregulated or downregulated under drought stress. Weighted co-expression network analysis (WGCNA) further identified four gene modules strongly correlated with drought-related phenotypes, co-localizing 2859 drought-responsive genes through both approaches. Proteomics and metabolomics were supplemented at the booting stage, where phenotypic and transcriptomic differences under drought were most pronounced. Integrated omics results demonstrate gibberellin (GA) and abscisic acid (ABA) pathways play a key role during drought tolerance in rice, and 79 high-confidence drought-resistant candidate genes were prioritized from the 2859 drought-responsive genes. Among these, Gibberellin 20-oxidase 5 (OsGA20ox5) was identified as a key negative regulator of drought tolerance. Furthermore, the transcription factor zinc finger protein 252 (OsZFP252) directly binds to the OsGA20ox5 promoter, repressing its expression and enhancing ABA biosynthesis, thereby improving drought tolerance by increasing stomatal closure and expanding vascular bundle water transport capacity. Notably, the drought-tolerant haplotype 2-4 (Hap2-4) of OsGA20ox5 provides valuable insights for drought-resistant breeding.

Oryza↗

Metabolic engineering in the -omics era: elucidating and modulating regulatory networks.

The importance of regulatory control in metabolic processes is widely acknowledged, and several enquiries (both local and global) are being made in understanding regulation at various levels of the metabolic hierarchy. The wealth of biological information has enabled identifying the individual components (genes, proteins, and metabolites) of a biological system, and we are now in a position to understand the interactions between these components. Since phenotype is the net result of these interactions, it is immensely important to elucidate them not only for an integrated understanding of physiology, but also for practical applications of using biological systems as cell factories. We present some of the recent "-omics" approaches that have expanded our understanding of regulation at the gene, protein, and metabolite level, followed by analysis of the impact of this progress on the advancement of metabolic engineering. Although this review is by no means exhaustive, we attempt to convey our ideology that combining global information from various levels of metabolic hierarchy is absolutely essential in understanding and subsequently predicting the relationship between changes in gene expression and the resulting phenotype. The ultimate aim of this review is to provide metabolic engineers with an overview of recent advances in complementary aspects of regulation at the gene, protein, and metabolite level and those involved in fundamental research with potential hurdles in the path to implementing their discoveries in practical applications.

Bacteria↗