NPJ Systems Biology and Applications最新文献

T cells mediate pathogenesis of several autoimmune disorders by recognizing self-epitopes presented on Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) complex. The majority of autoantigens presented to T cells in various autoimmune disorders are not known, which has impeded autoantigen identification. Recent advances in immunopeptidomics have started to unravel the repertoire of antigenic epitopes presented on MHC. In several autoimmune diseases, immunopeptidomics has led to the identification of novel autoantigens and has enhanced our understanding of the mechanisms behind autoimmunity. Especially, immunopeptidomics has provided key evidence to explain the genetic risk posed by HLA alleles. In this review, we shed light on how immunopeptidomics can be leveraged to discover potential autoantigens. We highlight the application of immunopeptidomics in Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), and Rheumatoid Arthritis (RA). Finally, we highlight the practical considerations of implementing immunopeptidomics successfully and the technical challenges that need to be addressed. Overall, this review will provide an important context for using immunopeptidomics for understanding autoimmunity.

Challenges in drug development for rare diseases such as pulmonary arterial hypertension can be addressed through the use of mathematical modeling. In this study, a quantitative systems pharmacology model of pulmonary arterial hypertension pathophysiology and pharmacology was used to predict changes in pulmonary vascular resistance and six-minute walk distance in the context of oral treprostinil clinical studies. We generated a virtual population that spanned the range of clinical observations and then calibrated virtual patient-specific weights to match clinical trials. We then used this virtual population to predict the results of clinical trials on the basis of disease severity, dosing regimen, time since diagnosis, and co-administered background therapies. The virtual population captured the effect of changes in trial design and patient subpopulation on clinical response. We also demonstrated the virtual trial workflow's potential for enriching populations based on clinical biomarkers to increase likelihood of trial success.

Genome-scale metabolic models (GSMM) are commonly used to identify gene deletion sets that result in growth coupling and pairing product formation with substrate utilization and can improve strain performance beyond levels typically accessible using traditional strain engineering approaches. However, sustainable feedstocks pose a challenge due to incomplete high-resolution metabolic data for non-canonical carbon sources required to curate GSMM and identify implementable designs. Here we address a four-gene deletion design in the Pseudomonas putida KT2440 strain for the lignin-derived non-sugar carbon source, p-coumarate (p-CA), that proved challenging to implement. We examine the performance of the fully implemented design for p-coumarate to glutamine, a useful biomanufacturing intermediate. In this study glutamine is then converted to indigoidine, an alternative sustainable pigment and a model heterologous product that is commonly used to colorimetrically quantify glutamine concentration. Through proteomics, promoter-variation, and growth characterization of a fully implemented gene deletion design, we provide evidence that aromatic catabolism in the completed design is rate-limited by fumarase hydratase (FUM) enzyme activity in the citrate cycle and requires careful optimization of another fumarate hydratase protein (PP_0897) expression to achieve growth and production. A double sensitivity analysis also confirmed a strict requirement for fumarate hydratase activity in the strain where all genes in the growth coupling design have been implemented. Metabolic cross-feeding experiments were used to examine the impact of complete removal of the fumarase hydratase reaction and revealed an unanticipated nutrient requirement, suggesting additional functions for this enzyme. While a complete implementation of the design was achieved, this study highlights the challenge of completely inactivating metabolic reactions encoded by under-characterized proteins, especially in the context of multi-gene edits.

Coronavirus disease 2019 (COVID-19) presents a wide spectrum of symptoms, the causes of which remain poorly understood. This study explored the associations between autoantibodies (AABs), particularly those targeting G protein-coupled receptors (GPCRs) and renin‒angiotensin system (RAS) molecules, and the clinical manifestations of COVID-19. Using a cross-sectional analysis of 244 individuals, we applied multivariate analysis of variance, principal component analysis, and multinomial regression to examine the relationships between AAB levels and key symptoms. Significant correlations were identified between specific AABs and symptoms such as fever, muscle aches, anosmia, and dysgeusia. Notably, anti-AGTR1 antibodies, which contribute to endothelial glycocalyx (eGC) degradation, a process reversed by losartan, have emerged as strong predictors of core symptoms. AAB levels increased with symptom accumulation, peaking in patients exhibiting all four key symptoms. These findings highlight the role of AABs, particularly anti-AGTR1 antibodies, in determining symptom severity and suggest their involvement in the pathophysiology of COVID-19, including vascular complications.

We report the existence of deterministic patterns in statistical plots of single-cell transcriptomic data. We develop a theory showing that the patterns are neither artifacts introduced by the measurement process nor due to underlying biological mechanisms. Rather they naturally emerge from finite sample size effects. The theory precisely predicts the patterns in data from multiplexed error-robust fluorescence in situ hybridization and five different types of single-cell sequencing platforms.

Breast cancer prognosis is complicated by tumor heterogeneity. Traditional methods focus on cancer-specific gene signatures, but cross-cancer strategies that provide deeper insights into tumor homogeneity are rarely used. Immunotherapy, particularly immune checkpoint inhibitors, results from variable responses across cancers, offering valuable prognostic insights. We introduced a network-based transfer (NBT) of pan-cancer immunotherapy responses to enhance breast cancer prognosis using node embedding and heat diffusion algorithms, identifying gene signatures netNE and netHD. Our results showed that netHD and netNE outperformed seven established breast cancer signatures in prognostic metrics, with netHD excelling. All nine gene signatures were grouped into three clusters, with netHD and netNE enriching the immune-related interferon-gamma pathway. Stratifying TCGA patients into two groups based on netHD revealed significant immunological differences and variations in 20 of 50 cancer hallmarks, emphasizing immune-related markers. This approach leverages pan-cancer insights to enhance breast cancer prognosis, facilitating insight transfer and improving tumor homogeneity understanding.Abstract graph of network-based insights translating pan-cancer immunotherapy responses to breast cancer prognosis. This abstract graph illustrates the conceptual framework for transferring immunotherapy response insights from pan-cancer studies to breast cancer prognosis. It highlights the integration of PPI networks to bridge genetic data and clinical phenotypes. The network-based method facilitates the identification of prognostic gene signatures in breast cancer by leveraging immunotherapy response information, providing a novel perspective on tumor homogeneity and its implications for clinical outcomes.

Understanding transcriptional heterogeneity in cancer cells and its implication for treatment response is critical to identify how resistance occurs and may be targeted. Such heterogeneity can be captured by in vitro studies through clonal barcoding methods. We present TraCSED (Transformer-based modeling of Clonal Selection and Expression Dynamics), a dynamic deep learning approach for modeling clonal selection. Using single-cell gene expression and the fitness of barcoded clones, TraCSED identifies interpretable gene programs and the time points at which they are associated with clonal selection. When applied to cells treated with either giredestrant, a selective estrogen receptor (ER) antagonist and degrader, or palbociclib, a CDK4/6 inhibitor, pathways dynamically associated with resistance are revealed. For example, ER activity is associated with positive selection around day four under palbociclib treatment and this adaptive response can be suppressed by combining the drugs. Yet, in the combination treatment, one clone still emerged. Clustering based on partial least squares regression found that high baseline expression of both SNHG25 and SNCG genes was the primary marker of positive selection to co-treatment and thus potentially associated with innate resistance - an aspect that traditional differential analysis methods missed. In conclusion, TraCSED enables associating features with phenotypes in a time-dependent manner from scRNA-seq data.

Predicting the biological behavior and time to recurrence (TTR) of high-grade diffuse gliomas (HGG) after maximum safe neurosurgical resection and combined radiation and chemotherapy plays a pivotal role in planning clinical follow-up, selecting potentially necessary second-line treatment and improving the quality of life for patients diagnosed with a malignant brain tumor. The current standard-of-care (SoC) for HGG includes follow-up neuroradiological imaging to detect recurrence as early as possible and relies on several clinical, neuropathological, and radiological prognostic factors, which have limited accuracy in predicting TTR. In this study, using an in-silico analysis, we aim to improve predictive power for TTR by considering the role of (i) prognostically relevant information available through diagnostics used in the current SoC, (ii) advanced image-based information not currently part of the standard diagnostic workup, such as tumor-normal tissue interface (edge) features and quantitative data specific to biopsy positions within the tumor, and (iii) information on tumor-associated macrophages. In particular, we introduced a state-of-the-art spatio-temporal model of tumor-immune interactions, emphasizing the interplay between macrophages and glioma cells. This model serves as a synthetic reality for assessing the predictive value of various features. We generated a cohort of virtual patients based on our mathematical model. Each patient's dataset includes simulated T1Gd and Fluid-attenuated inversion recovery (FLAIR) MRI volumes. T1-weighted imaging highlights anatomical structures with high contrast, providing clear detail on brain morphology, whereas FLAIR suppresses fluid signals, improving the visualization of lesions near fluid-filled spaces, which is particularly helpful for identifying peritumoral edema. Additionally, we simulated results on macrophage density and proliferative activity, either in a specified part of the tumor, namely the tumor core or edge ("localized"), or unspecified ("non-localized"). To enhance the realism of our synthetic data, we imposed different levels of noise. Our findings reveal that macrophage density at the tumor edge contributed to a high predictive value of feature importance for the selected regression model. Moreover, there are lower MSE values for the "localized" biopsy in prediction accuracy toward recurrence post-resection compared with "non-localized" specimens in the noisy data. In conclusion, the results show that localized biopsies provided more information about tumor behavior, especially at the interface of tumor and normal tissue (Edge).

Interconnected feedback loops are prevalent across biological mechanisms, including cell fate transitions enabled by epigenetic mechanisms in carcinomas. However, the operating principles of these networks remain largely unexplored. Here, we identify numerous interconnected feedback loops implicated in cell lineage decisions, which we discover to be the hallmarks of lower- and higher-dimensional state space. We demonstrate that networks having higher centrality nodes have restricted state space while those with lower centrality nodes have higher dimensional state space. The topologically distinct networks with identical node or loop counts have different steady-state distributions, highlighting the crucial influence of network structure on emergent dynamics. Further, regardless of topology, networks with autoregulated nodes exhibit multiple steady states, thereby "liberating" network dynamics from absolute topological control. These findings unravel the design principles of multistable networks implicated in fate decisions and can have crucial implications in engineering or comprehending multi-fate decision circuits.

CITE-seq provides a powerful method for simultaneously measuring RNA and protein expression at the single-cell level. The integrated analysis of RNA and protein expression in identical cells is crucial for revealing cellular heterogeneity. However, the high experimental costs associated with CITE-seq limit its widespread application. In this paper, we propose scTEL, a deep learning framework based on Transformer encoder layers, to establish a mapping from sequenced RNA expression to unobserved protein expression in the same cells. This computation-based approach significantly reduces the experimental costs of protein expression sequencing. We are now able to predict protein expression using single-cell RNA sequencing (scRNA-seq) data, which is well-established and available at a lower cost. Moreover, our scTEL model offers a unified framework for integrating multiple CITE-seq datasets, addressing the challenge posed by the partial overlap of protein panels across different datasets. Empirical validation on public CITE-seq datasets demonstrates scTEL significantly outperforms existing methods.