Hum Vaccin Immunother. 2023 Dec 15;19(3):2282803. doi: 10.1080/21645515.2023.2282803. Epub 2023 Dec 15.

ABSTRACT

A significant surge in research endeavors leverages the vast potential of high-throughput omic technology platforms for broad profiling of biological responses to vaccines and cutting-edge immunotherapies and stem-cell therapies under development. These profiles capture different aspects of core regulatory and functional processes at different scales of resolution from molecular and cellular to organismal. Systems approaches capture the complex and intricate interplay between these layers and scales. Here, we summarize experimental data modalities, for characterizing the genome, epigenome, transcriptome, proteome, metabolome, and antibody-ome, that enable us to generate large-scale immune profiles. We also discuss machine learning and network approaches that are commonly used to analyze and integrate these modalities, to gain insights into correlates and mechanisms of natural and vaccine-mediated immunity as well as therapy-induced immunomodulation.

PMID:38100557 | DOI:10.1080/21645515.2023.2282803

PLoS Comput Biol. 2023 Dec 15;19(12):e1011187. doi: 10.1371/journal.pcbi.1011187. Online ahead of print.

ABSTRACT

Quarantine has been long used as a public health response to emerging infectious diseases, particularly at the onset of an epidemic when the infected proportion of a population remains identifiable and logistically tractable. In theory, the same logic should apply to low-incidence infections; however, the application and impact of quarantine in low prevalence settings appears less common and lacks a formal analysis. Here, we present a quantitative framework using a series of progressively more biologically realistic models of canine rabies in domestic dogs and from dogs to humans, a suitable example system to characterize dynamical changes under varying levels of dog quarantine. We explicitly incorporate health-seeking behaviour data to inform the modelling of contact-tracing and exclusion of rabies suspect and probable dogs that can be identified through bite-histories of patients presenting at anti-rabies clinics. We find that a temporary quarantine of rabies suspect and probable dogs provides a powerful tool to curtail rabies transmission, especially in settings where optimal vaccination coverage is yet to be achieved, providing a critical stopgap to reduce the number of human and animal deaths due to rabid bites. We conclude that whilst comprehensive measures including sensitive surveillance and large-scale vaccination of dogs will be required to achieve disease elimination and sustained freedom given the persistent risk of rabies re-introductions, quarantine offers a low-cost community driven solution to intersectoral health burden.

PMID:38100528 | DOI:10.1371/journal.pcbi.1011187

Plant J. 2023 Dec 15. doi: 10.1111/tpj.16582. Online ahead of print.

ABSTRACT

Mutant populations are crucial for functional genomics and discovering novel traits for crop breeding. Sorghum, a drought and heat-tolerant C4 species, requires a vast, large-scale, annotated, and sequenced mutant resource to enhance crop improvement through functional genomics research. Here, we report a sorghum large-scale sequenced mutant population with 9.5 million ethyl methane sulfonate (EMS)-induced mutations that covered 98% of sorghum's annotated genes using inbred line BTx623. Remarkably, a total of 610 320 mutations within the promoter and enhancer regions of 18 000 and 11 790 genes, respectively, can be leveraged for novel research of cis-regulatory elements. A comparison of the distribution of mutations in the large-scale mutant library and sorghum association panel (SAP) provides insights into the influence of selection. EMS-induced mutations appeared to be random across different regions of the genome without significant enrichment in different sections of a gene, including the 5' UTR, gene body, and 3'-UTR. In contrast, there were low variation density in the coding and UTR regions in the SAP. Based on the Ka /Ks value, the mutant library (~1) experienced little selection, unlike the SAP (0.40), which has been strongly selected through breeding. All mutation data are publicly searchable through SorbMutDB (https://www.depts.ttu.edu/igcast/sorbmutdb.php) and SorghumBase (https://sorghumbase.org/). This current large-scale sequence-indexed sorghum mutant population is a crucial resource that enriched the sorghum gene pool with novel diversity and a highly valuable tool for the Poaceae family, that will advance plant biology research and crop breeding.

PMID:38100514 | DOI:10.1111/tpj.16582

Protein Sci. 2023 Dec 15:e4869. doi: 10.1002/pro.4869. Online ahead of print.

ABSTRACT

Protein function annotation and drug discovery often involve finding small molecule binders. In the early stages of drug discovery, virtual ligand screening (VLS) is frequently applied to identify possible hits before experimental testing. While our recent ligand homology modeling (LHM)-machine learning VLS method FRAGSITE outperformed approaches that combined traditional docking to generate protein-ligand poses and deep learning scoring functions to rank ligands, a more robust approach that could identify a more diverse set of binding ligands is needed. Here, we describe FRAGSITE2 that shows significant improvement on protein targets lacking known small molecule binders and no confident LHM identified template ligands when benchmarked on two commonly used VLS datasets: For both the DUD-E set and DEKOIS2.0 set and ligands having a Tanimoto Coefficient (TC) <0.7 to the template ligands, the 1% enrichment factor (EF1% ) of FRAGSITE2 is significantly better than those for FINDSITEcomb2.0, an earlier LHM algorithm. For the DUD-E set, FRAGSITE2 also shows better ROC enrichment factor and AUPR than the deep learning DenseFS scoring function. Comparison with the RF-score-VS on the 76 target subset of DEKOIS2.0 and a TC<0.99 to training DUD-E ligands, FRAGSITE2 has double the EF1% . Its boosted tree regression method provides for more robust performance than a deep learning multiple layer perceptron method. When compared to the pretrained language model for protein target features, FRAGSITE2 also shows much better performance. Thus, FRAGSITE2 is a promising approach that can discover novel hits for protein targets. FRAGSITE2's web service is freely available to academic users at http://sites.gatech.edu/cssb/FRAGSITE2. This article is protected by copyright. All rights reserved.

PMID:38100293 | DOI:10.1002/pro.4869

Am J Physiol Heart Circ Physiol. 2023 Dec 15. doi: 10.1152/ajpheart.00735.2023. Online ahead of print.

ABSTRACT

Pulmonary and systemic congestion as a consequence of heart failure are clinically recognized as alarm signals for clinical outcome and mortality. Whereas signs and symptoms of congestion are well detectable in patients, monitoring of congestion in small animals with heart failure lacks adequate non-invasive methodology yet. Here, we developed a novel ultrasonography-based scoring system to assess pulmonary and systemic congestion in experimental heart failure, by using lung ultrasound (LUS) and imaging of the inferior vena cava (Cava), termed CavaLUS. CavaLUS was established and tested in a rat model of supracoronary aortic banding, and a mouse model of myocardial infarction, providing high sensitivity and specificity while correlating to numerous parameters of cardiac performance and disease severity. CavaLUS therefore provides a novel comprehensive tool for experimental heart failure in small animals to non-invasively assess congestion.

PMID:38099848 | DOI:10.1152/ajpheart.00735.2023

Microbiol Spectr. 2023 Dec 15:e0196423. doi: 10.1128/spectrum.01964-23. Online ahead of print.

ABSTRACT

Horizontal gene transfer (HGT) is a key driver in the evolution of bacterial genomes. The acquisition of genes mediated by HGT may enable bacteria to adapt to ever-changing environmental conditions. Long-term application of antibiotics in intensive agriculture is associated with the dissemination of antibiotic resistance genes among bacteria with the consequences causing public health concern. Commensal farm-animal-associated gut microbiota are considered the reservoir of the resistance genes. Therefore, in this study, we identified known and not-yet characterized mobilized genes originating from chicken and porcine fecal samples using our innovative pipeline followed by network analysis to provide appropriate visualization to support proper interpretation.

PMID:38099617 | DOI:10.1128/spectrum.01964-23

J Clin Invest. 2023 Dec 15;133(24):e171199. doi: 10.1172/JCI171199.

ABSTRACT

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3βHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3βHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3βHSD1 inhibitors as early intervention.

PMID:38099500 | DOI:10.1172/JCI171199

J Physiol. 2023 Dec 15. doi: 10.1113/JP285349. Online ahead of print.

ABSTRACT

Accumulated fat in skeletal muscle (i.e. myosteatosis), common in sedentary older individuals, compromises skeletal muscle health and function. A mechanistic understanding of how physical activity levels dictate fat accumulation represents a critical step towards establishment of therapies that promote healthy ageing. Using a network medicine paradigm that characterized the transcriptomic response of aged muscle to exercise versus immobilization protocols, this study explored the shared molecular cascade that regulates the fate of fibro-adipogenic progenitors (FAPs), the cell population primarily responsible for fat accumulation. Specifically, gene set enrichment analyses with network propagation revealed Pgc-1α as a functional hub of a large gene regulatory network underlying the regulation of FAPs by physical activity in aged muscle, but not in young counterparts. Integrated in silico and in situ approaches to induce Pgc-1α overexpression in aged muscle promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. These findings suggest that the Pgc-1α-mitochondrial fatty acid oxidation axis is a shared mechanism by which physical activity regulates age-related myosteatosis. The network medicine paradigm introduced provides mechanistic insight into exercise adaptation in elderly skeletal muscle and offers translational opportunities to advance exercise prescription for older populations. KEY POINTS: Fat accumulation is a quintessential feature of aged skeletal muscle. While increasing physical activity levels has been proposed as an effective strategy to reduce the fat in skeletal muscle (i.e. myosteatosis), the molecular cascade underlying these benefits has been poorly defined. This study implemented a series of network medicine approaches and uncovered Pgc-1α as a mechanistic driver of the regulation of fibro-adipogenic progenitors (FAPs) by physical activity. Integrated in silico and in situ approaches to induce Pgc-1α overexpression promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. Together, the findings of the current study suggest a novel hypothesis that physical activity reduces myosteatosis via upregulation of Pgc-1α-mediated mitochondrial fatty acid oxidation and subsequent inhibition of FAP adipogenesis.

PMID:38099335 | DOI:10.1113/JP285349

Cancer Res. 2023 Dec 15;83(24):4047-4062. doi: 10.1158/0008-5472.CAN-22-2483.

ABSTRACT

Identifying novel cell surface receptors that regulate leukemia cell differentiation and can be targeted to inhibit cellular proliferation is crucial to improve current treatment modalities in acute myeloid leukemia (AML), especially for relapsed or chemotherapy-refractory leukemia. Leukocyte immunoglobulin-like receptor type B (LILRB) is an immunomodulatory receptor originally found to be expressed in myeloid cells. In this study, we found that LILRB receptors can be induced under inflammatory stimuli and chemotherapy treatment conditions. Blockade of LILRB3 inhibited leukemia cell proliferation and leukemia progression. In addition, treatment with LILRB3 blocking antibodies upregulated myeloid lineage differentiation transcription factors, including PU.1, C/EBP family, and IRF, whereas phosphorylation of proliferation regulators, for example, AKT, cyclin D1, and retinoblastoma protein, was decreased. Conversely, transcriptomic analysis showed LILRB3 activation by agonist antibodies may enhance leukemia survival through upregulation of cholesterol metabolism, which has been shown to promote leukemia cell survival. Moreover, LILRB3-targeted CAR T cells exhibited potent antitumor effects both in vitro and in vivo. Taken together, our results suggest that LILRB3 is a potentially potent target for multiple treatment modalities in AML.

SIGNIFICANCE: LILRB3 regulates differentiation and proliferation in acute myeloid leukemia and can be targeted with monoclonal antibodies and CAR T cells to suppress leukemia growth.

PMID:38098451 | DOI:10.1158/0008-5472.CAN-22-2483

Kidney360. 2023 Dec 15. doi: 10.34067/KID.0000000000000345. Online ahead of print.

ABSTRACT

BACKGROUND: The aberrant glucose circadian rhythm is associated with the pathogenesis of diabetes. Similar to glucose metabolism in kidney and liver, d-alanine, a rare enantiomer of alanine, shows circadian alteration, although the effect of d-alanine on glucose metabolism has not been explored. Here we show that d-alanine acts on the circadian clock and affects glucose metabolism in the kidney.

METHODS: The blood and urinary levels of d-alanine in mice were measured using two-dimensional high performance liquid chromatography system. Metabolic effects of d-alanine were analysed in mice and in primary culture of kidney proximal tubular cells from mice. Behavioural and gene expression analyses of circadian rhythm were performed using mice bred under constant darkness.

RESULTS: d-Alanine levels in blood exhibited a clear intrinsic circadian rhythm. Since this rhythm was regulated by the kidney through urinary excretion, we examined the effect of d-alanine on kidney. In kidney, d-alanine induced expressions of genes involved in gluconeogenesis and circadian rhythm. Treatment of d-alanine mediated glucose production in mice. Ex vivo glucose production assay demonstrated that treatment of d-alanine induced glucose production in primary culture of kidney proximal tubular cells, where d-amino acids are known to be reabsorbed, but not in that of liver cells. Gluconeogenetic effect of d-alanine has an intraday variation, and this effect was in part mediated through circadian transcriptional network. Under constant darkness, treatment of d-alanine normalized the circadian cycle of behaviour and kidney gene expressions.

CONCLUSIONS: d-Alanine induces gluconeogenesis in the kidney and adjusts the period of the circadian clock. Normalization of circadian cycle by d-alanine may provide the therapeutic options for life style-related diseases and shift workers.

PMID:38098136 | DOI:10.34067/KID.0000000000000345

BMC Bioinformatics. 2023 Dec 14;24(1):475. doi: 10.1186/s12859-023-05588-3.

ABSTRACT

BACKGROUND: The standardization of biological data using unique identifiers is vital for seamless data integration, comprehensive interpretation, and reproducibility of research findings, contributing to advancements in bioinformatics and systems biology. Despite being widely accepted as a universal identifier, scientific names for biological species have inherent limitations, including lack of stability, uniqueness, and convertibility, hindering their effective use as identifiers in databases, particularly in natural product (NP) occurrence databases, posing a substantial obstacle to utilizing this valuable data for large-scale research applications.

RESULT: To address these challenges and facilitate high-throughput analysis of biological data involving scientific names, we developed PhyloSophos, a Python package that considers the properties of scientific names and taxonomic systems to accurately map name inputs to entries within a chosen reference database. We illustrate the importance of assessing multiple taxonomic databases and considering taxonomic syntax-based pre-processing using NP occurrence databases as an example, with the ultimate goal of integrating heterogeneous information into a single, unified dataset.

CONCLUSIONS: We anticipate PhyloSophos to significantly aid in the systematic processing of poorly digitized and curated biological data, such as biodiversity information and ethnopharmacological resources, enabling full-scale bioinformatics analysis using these valuable data resources.

PMID:38097955 | DOI:10.1186/s12859-023-05588-3

Nature. 2023 Dec 14. doi: 10.1038/s41586-023-06947-z. Online ahead of print.

ABSTRACT

The LINE-1 (L1) retrotransposon is an ancient genetic parasite that has written around one third of the human genome through a "copy-and-paste" mechanism catalyzed by its multifunctional enzyme, open reading frame 2 protein (ORF2p)1. ORF2p reverse transcriptase (RT) and endonuclease activities have been implicated in the pathophysiology of cancer2,3, autoimmunity4,5, and aging6,7, making ORF2p a potential therapeutic target. However, a lack of structural and mechanistic knowledge has hampered efforts to rationally exploit it. We report structures of the human ORF2p 'core' (residues 238-1061, including the RT domain) by X-ray crystallography and cryo-EM in multiple conformational states. Our analyses reveal two novel folded domains, extensive contacts to RNA templates, and associated adaptations that contribute to unique aspects of the L1 replication cycle. Computed integrative structural models of full-length ORF2p show a dynamic closed ring conformation that appears to open during retrotransposition. We characterize ORF2p RT inhibition and reveal its underlying structural basis. Imaging and biochemistry reveal that non-canonical cytosolic ORF2p RT activity can produce RNA:DNA hybrids, activating innate immune signaling via cGAS/STING and resulting in interferon production6-8. In contrast to retroviral RTs, L1 RT is efficiently primed by short RNAs and hairpins, which likely explains cytosolic priming. Additional biochemical activities including processivity, DNA-directed polymerization, non-templated base addition, and template switching together allow us to propose an updated L1 insertion model. Finally, our evolutionary analysis reveals structural conservation between ORF2p and other RNA- and DNA-dependent polymerases. We therefore provide key mechanistic insights into L1 polymerization and insertion, shed light on L1 evolutionary history, and enable rational drug development targeting L1.

PMID:38096902 | DOI:10.1038/s41586-023-06947-z

Nat Genet. 2023 Dec 14. doi: 10.1038/s41588-023-01610-9. Online ahead of print.

NO ABSTRACT

PMID:38097705 | DOI:10.1038/s41588-023-01610-9

Nat Commun. 2023 Dec 14;14(1):8210. doi: 10.1038/s41467-023-43448-z.

ABSTRACT

Prebiotics are defined as non-digestible dietary components that promote the growth of beneficial gut microorganisms. In many cases, however, this capability is not systematically evaluated. Here, we develop a methodology for determining prebiotic-responsive bacteria using the popular dietary supplement inulin. We first identify microbes with a capacity to bind inulin using mesoporous silica nanoparticles functionalized with inulin. 16S rRNA gene amplicon sequencing of sorted cells revealed that the ability to bind inulin was widespread in the microbiota. We further evaluate which taxa are metabolically stimulated by inulin and find that diverse taxa from the phyla Firmicutes and Actinobacteria respond to inulin, and several isolates of these taxa can degrade inulin. Incubation with another prebiotic, xylooligosaccharides (XOS), in contrast, shows a more robust bifidogenic effect. Interestingly, the Coriobacteriia Eggerthella lenta and Gordonibacter urolithinfaciens are indirectly stimulated by the inulin degradation process, expanding our knowledge of inulin-responsive bacteria.

PMID:38097563 | DOI:10.1038/s41467-023-43448-z

Trends Biochem Sci. 2023 Dec 14:S0968-0004(23)00277-3. doi: 10.1016/j.tibs.2023.10.008. Online ahead of print.

ABSTRACT

The uridine modifications pseudouridine (Ψ), dihydrouridine, and 5-methyluridine are present in eukaryotic mRNAs. Many uridine-modifying enzymes are associated with human disease, underscoring the importance of uncovering the functions of uridine modifications in mRNAs. These modified uridines have chemical properties distinct from those of canonical uridines, which impact RNA structure and RNA-protein interactions. Ψ, the most abundant of these uridine modifications, is present across (pre-)mRNAs. Recent work has shown that many Ψs are present at intermediate to high stoichiometries that are likely conducive to function and at locations that are poised to influence pre-/mRNA processing. Technological innovations and mechanistic investigations are unveiling the functions of uridine modifications in pre-mRNA splicing, translation, and mRNA stability, which are discussed in this review.

PMID:38097411 | DOI:10.1016/j.tibs.2023.10.008

Bioinformatics. 2023 Dec 14:btad753. doi: 10.1093/bioinformatics/btad753. Online ahead of print.

ABSTRACT

MOTIVATION: Developing biochemical models in systems biology is a complex, knowledge-intensive activity. Some modelers (especially novices) benefit from model development tools with a graphical user interface (GUI). However, as with the development of complex software, text-based representations of models provide many benefits for advanced model development. At present, the tools for text-based model development are limited, typically just a textual editor that provides features such as copy, paste, find, and replace. Since these tools are not "model aware", they do not provide features for: (i) model building such as autocompletion of species names; (ii) model analysis such as hover messages that provide information about chemical species; and (iii) model translation to convert between model representations. We refer to these as BAT features.

RESULTS: We present VSCode-Antimony, a tool for building, analyzing, and translating models written in the Antimony modeling language, a human readable representation of SBML models. VSCode-Antimony is a source editor, a tool with language-aware features. For example, there is autocompletion of variable names to assist with model building, hover messages that aid in model analysis, and translation between XML and Antimony representations of SBML models. These features result from making VSCode-Antimony model-aware by incorporating several sophisticated capabilities: analysis of the Antimony grammar (e.g., to identify model symbols and their types); a query system for accessing knowledge sources for chemical species and reactions; and automatic conversion between different model representations (e.g., between Antimony and SBML).

AVAILABILITY: VSCode-Antimony is available as an open source extension in the VSCode Marketplace https://marketplace.visualstudio.com/items?itemName=stevem.vscode-antimony. Source code can be found at https://github.com/sys-bio/vscode-antimony.

SUPPLEMENTARY INFORMATION: Documentation and downloads are available at the visual studio marketplace.

PMID:38096590 | DOI:10.1093/bioinformatics/btad753

JCO Precis Oncol. 2023 Sep;7:e2300287. doi: 10.1200/PO.23.00287.

NO ABSTRACT

PMID:38096470 | DOI:10.1200/PO.23.00287

PLoS One. 2023 Dec 14;18(12):e0295863. doi: 10.1371/journal.pone.0295863. eCollection 2023.

ABSTRACT

Immunotherapy is changing the Head and Neck Squamous Cell Carcinoma (HNSCC) landscape and improving outcomes for patients with recurrent or metastatic HNSCC. A deeper understanding of the tumor microenvironment (TME) is required in light of the limitations of patients' responses to immunotherapy. Here, we aimed to examine how Nivolumab affects infiltrating Tregs in the HNSCC TME. We used single-cell RNA sequencing data from eight tissues isolated from four HNSCC donors before and after Nivolumab treatment. Interestingly, the study found that Treg counts and suppressive activity increased following Nivolumab therapy. We also discovered that changes in the CD44-SSP1 axis, NKG2C/D-HLA-E axis, and KRAS signaling may have contributed to the increase in Treg numbers. Furthermore, our study suggests that decreasing the activity of the KRAS and Notch signaling pathways, and increasing FOXP3, CTLA-4, LAG-3, and GZMA expression, may be mechanisms that enhance the killing and suppressive capacity of Tregs. Additionally, the result of pseudo-temporal analysis of the HNSCC TME indicated that after Nivolumab therapy, the expression of certain inhibitory immune checkpoints including TIGIT, ENTPD1, and CD276 and LY9, were decreased in Tregs, while LAG-3 showed an increased expression level. The study also found that Tregs had a dense communication network with cluster two, and that certain ligand-receptor pairs, including SPP1/CD44, HLA-E/KLRC2, HLA-E/KLRK1, ANXA1/FPR3, and CXCL9/FCGR2A, had notable changes after the therapy. These changes in gene expression and cell interactions may have implications for the role of Tregs in the TME and in response to Nivolumab therapy.

PMID:38096229 | DOI:10.1371/journal.pone.0295863

Cell Rep. 2023 Dec 12;42(12):113561. doi: 10.1016/j.celrep.2023.113561. Online ahead of print.

ABSTRACT

Quiescence is a common cellular state, required for stem cell maintenance and microorganismal survival under stress conditions or starvation. However, the mechanisms promoting quiescence maintenance remain poorly known. Plasma membrane components segregate into distinct microdomains, yet the role of this compartmentalization in quiescence remains unexplored. Here, we show that flavodoxin-like proteins (FLPs), ubiquinone reductases of the yeast eisosome membrane compartment, protect quiescent cells from lipid peroxidation and ferroptosis. Eisosomes and FLPs expand specifically in respiratory-active quiescent cells, and mutants lacking either show accelerated aging and defective quiescence maintenance and accumulate peroxidized phospholipids with monounsaturated or polyunsaturated fatty acids (PUFAs). FLPs are essential for the extramitochondrial regeneration of the lipophilic antioxidant ubiquinol. FLPs, alongside the Gpx1/2/3 glutathione peroxidases, prevent iron-driven, PUFA-dependent ferroptotic cell death. Our work describes ferroptosis-protective mechanisms in yeast and introduces plasma membrane compartmentalization as an important factor in the long-term survival of quiescent cells.

PMID:38096056 | DOI:10.1016/j.celrep.2023.113561

Nucleic Acids Res. 2023 Dec 14:gkad1187. doi: 10.1093/nar/gkad1187. Online ahead of print.

ABSTRACT

Pathway analysis, including nontopology-based (non-TB) and topology-based (TB) methods, is widely used to interpret the biological phenomena underlying differences in expression data between two phenotypes. By considering dependencies and interactions between genes, TB methods usually perform better than non-TB methods in identifying pathways that include closely relevant or directly causative genes for a given phenotype. However, most TB methods may be limited by incomplete pathway data used as the reference network or by difficulties in selecting appropriate reference networks for different research topics. Here, we propose a gene set correlation enrichment analysis method, Gscore, based on an expression dataset-derived coexpression network to examine whether a differentially expressed gene (DEG) list (or each of its DEGs) is associated with a known gene set. Gscore is better able to identify target pathways in 89 human disease expression datasets than eight other state-of-the-art methods and offers insight into how disease-wide and pathway-wide associations reflect clinical outcomes. When applied to RNA-seq data from COVID-19-related cells and patient samples, Gscore provided a means for studying how DEGs are implicated in COVID-19-related pathways. In summary, Gscore offers a powerful analytical approach for annotating individual DEGs, DEG lists, and genome-wide expression profiles based on existing biological knowledge.

PMID:38096046 | DOI:10.1093/nar/gkad1187