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PubMed2025

Cross-feeding percolation phase transitions of intercellular metabolic networks.

Intercellular cross-talk is essential for the adaptation capabilities of populations of cells. While direct diffusion-driven cell-to-cell exchanges are difficult to map, current nanotechnology enables one to probe single-cell exchanges with the medium. We introduce a mathematical method to reconstruct the dynamic unfolding of intercellular exchange networks from these data, applying it to an experimental coculture system. The exchange network, initially dense, progressively fragments into small disconnected clusters. To explain these dynamics, we develop a maximum-entropy multicellular metabolic model with diffusion-driven exchanges. The model predicts a transition from a dense network to a sparse one as nutrient consumption shifts. We characterize this crossover both numerically, revealing a power-law decay in the cluster-size distribution, and analytically, by connecting to percolation theory. Comparison with data suggests that populations evolve toward the sparse phase by remaining near the crossover. These findings offer insights into the collective organization driving the adaptive dynamics of cell populations.

Metabolic Networks and Pathways↗
PubMed2025

Flux-sum coupling analysis of metabolic network models.

Metabolites acting as substrates and regulators of all biochemical reactions play an important role in maintaining the functionality of cellular metabolism. Despite advances in the constraint-based framework for genome-scale metabolic modeling, we lack reliable proxies for metabolite concentrations that can be efficiently determined and that allow us to investigate the relationship between metabolite concentrations in specific metabolic states in the absence of measurements. Here, we introduce a constraint-based approach, the flux-sum coupling analysis (FSCA), which facilitates the study of the interdependencies between metabolite concentrations by determining coupling relationships based on the flux-sum of metabolites. Application of FSCA on metabolic models of Escherichia coli, Saccharomyces cerevisiae, and Arabidopsis thaliana showed that the three coupling relationships are present in all models and pinpointed similarities in coupled metabolite pairs. Using the available concentration measurements of E. coli metabolites, we demonstrated that the coupling relationships identified by FSCA can capture the qualitative associations between metabolite concentrations and that flux-sum is a reliable proxy for metabolite concentration. Therefore, FSCA provides a novel tool for exploring and understanding the intricate interdependencies between the metabolite concentrations, advancing the understanding of metabolic regulation, and improving flux-centered systems biology approaches.

Escherichia coli↗
PubMed1976

Regulation of rat adrenal dopamine beta-hydroxylase. II. Receptor interaction in the regulation of enzyme synthesis and degradation.

Rat adrenal gland dopamine beta-hydroxylase is under neuronal regulation from the splanchnic nerve and hormonal control via adrenal cortical glucocorticoids. The regulatory systems act in different ways; neuronal stimuli induce dopamine beta-hydroxylase synthesis while hormonal stimulation inhibits enzyme degradation. Despite these mechanistic differences, both systems require a normally innervated cholinergic receptor to exert their effect. The enzyme response to either neural stimulation or ACTH administration is blocked by splanchnic denervation. Glucocorticoid stimulation of dopamine beta-hydroxylase, however, can occur after adrenal denervation, suggesting that ACTH acts on a receptor which requires splanchnic innervation, but glucocorticoids act distal to the receptor. Similar results were obtained when the effect of these manipulations were studied on phenylethanolamine N-methyltransferase, another enzyme in the catecholamine biosynthetic pathway. A model attempting to unify these and earlier findings is presented, in which the splanchnic nerve is involved in regulating both adrenal cortical glucocorticoidogenesis (by allowing ACTH to act on glucocorticoid synthesis) and adrenal medullary catecholamine biosynthesis (by induction of enzyme synthesis.).

Adrenal Glands↗
PubMed2019

Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine-activated human aortic endothelial cells - Novel qualification markers for chronic disease risk factors and conditional DAMPs.

To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245).

Acetylation↗
PubMed2026

Exploring biohydrogen producing potential of Arctic ice and water through metagenomics and dark fermentation kinetics.

Cryospheric ecosystems in the high Arctic harbor largely unexplored microbiomes with significant biotechnological potential. The present study evaluates the biohydrogen production capabilities of the indigenous microbiome of Ny-Ålesund, Svalbard, using glacial ice and surface water samples. Dark fermentation batch assays were performed at 4 °C and 20 °C with 2-bromoethanesulfonate (BES), a methanogenic inhibitor, to track the succession of metabolic and taxonomic diversity. Metagenomic and functional analyses revealed that under 20 °C and BES conditions, psychrotolerant microbial communities maximize biohydrogen production to 85% of the total biogas produced, with an acetate-dominant fermentation pathway, as inferred from volatile fatty acid (VFA) analysis. This evolves into a highly coordinated system utilizing a coupled Rnf-nitrogenase route alongside Formate Hydrogenlyase and [FeFe]-hydrogenase pathways. Kinetic modelling using the Modified Gompertz equation, along with Q10 temperature-sensitivity indices, demonstrated a very high latent catalytic potential in these cold-adapted microbiomes. This study indicates that Arctic microbiomes are highly elastic thermodynamically and could serve as highly efficient, manipulatable biocatalysts for the environmental recovery of bioenergy through engineered low-temperature systems.

Fermentation↗
PubMed1979

Mutagenesis and embryonal carcinogenesis.

The embryonal tumors of children occur in dominantly heritable and nonhereditary forms, which indicates that a dominant mutation can be on the carcinogenic pathway. A model which fits age-specific incidence hypothesizes that both forms arise as a consequence of two mutations. The background incidences of these tumors then reflect spontaneous mutation rates in germinal and somatic cells and may be increased by mutagens. The gene for one tumor (retinoblastoma) seems to be located on chromosome 13. Clues to the pathophysiology of these tumor genes come from consideration of their tissue specificity, origin from embryonal cells, and developmental effects. Childhood cancers may be manifestations of the homozygous states of a series of genes concerned with differentiation in specific embryonal tissues.

Child↗
PubMed1975

The response of oscillating glycolysis to perturbations in the NADH/NAD system: a comparison between experiments and a computer model.

The glycolytic pathway is described by a set of coupled non linear differential equations of first order with respect to time. The individual terms of these equations consist of enzyme velocities assuming a steady state hypothesis for the enzymatic forms. These are specified and the system is solved numerically. Oscillations are explained by interaction of PFK with the adenylate system. The conditions for the occurrence of oscillations are tested in a series of computer runs. The phase relations between intermediates of the model agree with those found in yeast cells. As an application of the model the disturbation of oscillations by the addition of acetaldehyde is simulated. The predictions of the model agree with experimental results.

Acetaldehyde↗
PubMed1975

Biochemical mapping of the noradrenergic projection from the locus coeruleus. A model for studies of brain neuronal pathways.

Mapping of the noradrenergic projection from neurons in the rat locus coeruleus has been examined by combining a sensitive radioisotopic assay for catecholamines with a microdissection technique to remove multiple separate brain nuclei. The effect of a unilateral locus coeruleus lesion on norepinephrine concentration in 19 brain regions ipsilateral and contralateral to the lesion was determined. Evidence for ipsilateral and bilateral innervation to specific regions is presented, and many regions appear to receive combined innervation from other noradrenergic loci, in addition to that from the locus coeruleus. Fluorescence rating was correlated with biochemical measurement of amine content with these techniques and proportionality was observed over a narrow range. With this proportionality taken into consideration, mapping results obtained by biochemical and fluorescence methods are compared.

Animals↗
PubMed2026

Knowledge-driven interpretable neural networks provide mechanistic insight.

Analyzing omics data in the context of pathway knowledge is critical for understanding the molecular mechanisms underlying pathological changes. However, current pathway analysis methods do not model the detailed mechanistic nature of biological interactions, limiting the understanding of pathway behavior to a relatively shallow level. To address this issue, we present a knowledge-driven machine learning framework that embeds features into pathway graphs and models reactions analytically, producing interpretable feature hierarchies and subnetworks in which functional associations are estimated to model biological interactions. The approach is agnostic to feature selection, enabling the use of full omics data sets without discarding weak signals. Applications to breast cancer microRNA-gene regulation data and COVID-19 metabolomic data highlight immune and metabolic pathways relevant to disease progression. This framework bridges predictive modeling with mechanistic interpretation and offers a foundation for integrative pathway analysis.

Humans↗
PubMed2026

CeLLTra: aligning cell names with gene expression via a pathway-informed transformer.

MOTIVATION: Single-cell RNA sequencing (scRNA-Seq) technology enables detailed exploration of gene expression at the individual cell level, crucial for annotating cell types and understanding cellular diversity. Traditional methods for cell type annotation often rely on marker genes and manual labeling, posing challenges due to low data quality and incomplete reference datasets. RESULTS: We developed CeLLTra, a novel contrastive learning framework that leverages a Transformer-based model integrating biological pathway information to group genes into super tokens, effectively capturing comprehensive gene expression from scRNA-Seq data. By combining this pathway-informed Transformer with a pretrained domain-specific language model, CeLLTra accurately aligns cell-type annotations with gene expression profiles. Evaluations on a large-scale human scRNA-Seq dataset showed that CeLLTra significantly outperformed state-of-the-art methods in supervised and zero-shot cell-type prediction. Additionally, CeLLTra generalized well to external datasets, improving clustering performance and enabling better characterization of cancerous cell states in tumor-infiltrating myeloid cells from non-small cell lung cancer patients. AVAILABILITY AND IMPLEMENTATION: CeLLTra is freely available on GitHub (https://github.com/WJZheng-group/CeLLTra) and Zenodo (https://doi.org/10.5281/zenodo.17666735). The datasets underlying this article are the following: GSE201333 and GSE127465. All these datasets are publicly available and can be freely accessed on the Gene Expression Omnibus repository.

Humans↗
PubMed2026

Using deep learning models as a genetic architecture for the simulation of breeding schemes.

In several simulation studies, long-term selection led to the rapid depletion of genetic variance. These outcomes differ from real-life observations that we aim to replicate, thereby highlighting a fundamental limitation of current classical quantitative genetic simulation models. Deep learning (DL) models have demonstrated promising results in capturing complex interactions essential for maintaining genetic variance; thus, we hypothesize that DL-based genetic simulation models may preserve more genetic variance than classical models, because the biological pathways underlying complex traits exhibit interactions that classical models ignore. The primary objective of this study was to introduce alternative DL-based genetic simulation models and compare them with classical genetic simulation models in terms of their retention of additive genetic variance under truncation selection in a simulated full-sib pig breeding scheme using real haplotypes as founders. After 20 generations of directional truncation selection, the classical models (A, ADAA, and ADAAADDD) retained between 55% and 64% of their initial additive genetic variance. In contrast, while the DL_simple model lost all its additive variance, the DL medium retained 92% to 98% of its additive variance, and the DL_complex model's initial additive variance increased by 296% to 314%. This paper introduces DL-based genetic simulation models and concludes that their ability to retain additive genetic variance depends on the models' architectural complexity. When sufficiently complex, DL-based models exhibit greater retention of additive genetic variance because they intrinsically capture epistatic interactions that are converted into additive variance, as selection progresses, thus, affirming the role of non-additive genetic effects in maintaining long-term genetic variation.

Deep Learning↗
PubMed1979

Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects.

A model for the synthesis and degradation of very low density lipoprotein triglyceride (VLDL-TG) in man is proposed to explain plasma VLDL-TG radioactivity data from studies conducted over a 48-h interval after injection of glycerol labeled with 14C, 3H, or both. The curve describing the radioactivity of plasma VLDL triglycerides reaches a maximum at about 2 h, after which the decay is biphasic in all cases; the late curvature becoming evident only after 8--12 h. To fit the complex curve, it was necessary to postulate two pathways for the incorporation of plasma glycerol into VLDL-TG, one much slower than the other. A process of stepwise delipidation of VLDL in the plasma compartment, previously proposed for VLDL apoprotein models, was also necessary. Predicted VLDL-TG synthesis rates calculated with this model can differ significantly from those based on experiments of shorter duration in which the slow VLDL-TG component is not apparent. The results of these studies strongly support the interpretation that the late, slow component of the VLDL-TG activity curve is predominantly due to the slowly turning-over precursor compartment in the conversion pathway and is not due either to a slow compartment in the labeled precursor, plasma free glycerol, or to an exchange of plasma VLDL-TG with an extravascular compartment. It also cannot, in these studies, be attributed to a slowly turning-over VLDL-TG moiety in the plasma. The model was tested with data from 59 studies including normal subjects and patients with obesity and(or) various forms of hyperlipoproteinemia. Good fits were obtained in all cases, and the estimated parameter values and their uncertainties for 13 normolipemic nonobese subjects are presented. Sensitivty testing was carried out to determine how critical various parameter estimations are to the assumptions introduced in the modeling.

Glycerol↗
PubMed2026

Mechanisms of impact of mental health peer support in high-, middle- and low-income settings: mediation analysis of the UPSIDES randomised controlled trial.

AIMS: While there is growing evidence for the effectiveness of peer support (PS) in improving psychosocial outcomes among individuals with severe mental health conditions, the mechanisms through which these effects occur remain insufficiently understood. This study examines whether social inclusion, hope and empowerment mediate the relationship between PS, personal recovery and health and social functioning. METHODS: Data were collected from 565 adults with severe mental health conditions who participated in the multicentre UPSIDES randomised controlled trial across six sites in Germany, Uganda, Tanzania, India and Israel. Participants in the intervention group received structured PS from trained peer workers over a 6- to 8-month period. Standardised, self-report measures of social inclusion, hope, empowerment and personal recovery, as well as clinician-rated health and social functioning, were administered at baseline, 4&#xa0;months, end of intervention (8&#xa0;months) and 12-month follow-up. Cross-lagged panel modelling was used to explore longitudinal associations and mediating pathways. RESULTS: The cross-lagged models showed strong autoregressive effects across all variables, indicating high temporal stability. There were no significant direct effects of PS on recovery or health and social functioning. However, mediation analysis identified significant indirect effects of PS on personal recovery via social inclusion (&#x3b2;&#xa0;=&#xa0;0.114, 95% confidence interval [CI] [0.049, 0.194], P&#xa0;<&#xa0;0.05) and hope (&#x3b2;&#xa0;=&#xa0;0.037, 95% CI [0.001, 0.086], P&#xa0;<&#xa0;0.05). Similar indirect effects were observed for health and social functioning (via social inclusion: &#x3b2;&#xa0;=&#xa0;-0.035, 95% CI [-0.064,&#xa0;-0.013]; via hope: &#x3b2;&#xa0;=&#xa0;-0.026, 95% CI [-0.052, -0.006]; both P&#xa0;<&#xa0;0.05). CONCLUSIONS: Findings suggest that PS affects recovery-related outcomes primarily through intermediate mechanisms of enhanced hope and social inclusion. These results support theoretical models positing indirect pathways of change in PS interventions and highlight the value of targeting social and psychological domains when designing and implementing PS in mental health services. Individuals with lower baseline levels of hope and social inclusion may particularly benefit from PS.

Humans↗
PubMed2026

ITPRIPL1: A tumor immune-associated biomarker with prognostic and therapeutic implications in gastrointestinal cancer.

Inositol 1,4,5-trisphosphate receptor-interacting protein-like 1(ITPRIPL1) has recently been implicated in tumor-immune regulation, yet its tumor-type specificity and clinical relevance in gastrointestinal malignancies remain unclear. Here, we performed an integrative analysis of ITPRIPL1 across stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), rectal adenocarcinoma (READ), and esophageal carcinoma (ESCA) using bulk transcriptomics, immune pathway analyses, survival modeling, single-cell RNA sequencing, immunofluorescence validation, and therapeutic correlation analyses. Although ITPRIPL1 was upregulated across gastrointestinal cancers, its prognostic significance was highly tumor-specific, with elevated expression consistently predicting unfavorable survival only in STAD. In gastric cancer, ITPRIPL1 expression was closely associated with immune-related pathways and genomic instability features, and its prognostic association varied across immune contexts, particularly according to CD8&#x207a;/CD4&#x207a; T-cell abundance, with an exploratory association also observed for zeta-chain-associated protein kinase 70 (ZAP70) expression. Single-cell and immunofluorescence analyses demonstrated preferential enrichment of ITPRIPL1 in T cells and tumor-adjacent immune structures. Notably, Exploratory analyses further showed that higher ITPRIPL1 expression was associated with favorable survival outcomes in selected external pretreatment immunotherapy cohorts and with lower IC50 values for several agents in cancer cell-line pharmacogenomic datasets. Collectively, these findings identify ITPRIPL1 as an immune-associated biomarker with primary clinical relevance in gastric cancer.

Humans↗
PubMed2026

Transcriptomic Insights into Acupuncture Mechanisms in Protecting Ovarian Function in Mice with Premature Ovarian Insufficiency.

OBJECTIVE: To explore the molecular mechanisms underlying the protective effect of acupuncture on ovarian function in mice with cyclophosphamide-induced premature ovarian insufficiency (POI) via transcriptomic analysis. METHODS: Twenty female C57BL/6 mice were divided into 4 groups: control, model, acupuncture, and non-meridian/non-acupoint (NOMA). POI was induced in the model, acupuncture, and non-meridian/non-acupoint groups via cyclophosphamide injection. The acupuncture group received acupuncture at Guanyuan (CV 4), bilateral Guilai (ST 29), and Sanyinjiao (SP 6) for 3 weeks. After the intervention, ovarian tissue weight and ovarian coefficient were calculated, serum levels of key reproductive hormones including follicle-stimulating hormone (FSH), luteinizing hormone (LH) and anti-M&#xfc;llerian hormone (AMH) were detected, and ovarian histopathological changes were observed to evaluate ovarian function. Transcriptome sequencing was performed to identify differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to explore key functional terms and signaling pathways. Western blot was finally applied to validate the expression of core proteins related to mitochondrial function, endoplasmic reticulum stress and inflammatory pathways. RESULTS: The model group showed reduced ovarian weight and elevated FSH levels. The acupuncture group exhibited significantly higher ovarian weight and coefficient, lower FSH levels, and increased E2 and AMH levels compared to the model group (all P<0.01). Transcriptomic analysis revealed 4,021 DEGs between groups. GO and KEGG analyses revealed that these DEGs were mainly involved in oocyte development, steroid hormone synthesis, and pathways related to mitochondrial function, endoplasmic reticulum stress, and inflammatory signaling. Western blot analysis showed that acupuncture partially restored mitochondrial function markers cytochrome c oxidase subunit IV and NADH dehydrogenase 1 beta subcomplex subunit 8 and reduced endoplasmic reticulum stress markers (glucose-regulated protein 78 and Calnexin, P<0.01). It also downregulated pro-inflammatory proteins (IL-17R, IL-17A, NF-&#x3ba;B p65, p-NF-&#x3ba;B p65, ERK1/2, and p-ERK1/2) and upregulated proteins related to metabolic homeostasis (peroxisome proliferator-activated receptor &#x3b3;, receptor-interacting protein 140, nicotinamide phosphoribosyltransferase, and sirtuin 1, P<0.01). CONCLUSION: Acupuncture effectively alleviates cyclophosphamide-induced POI in mice, improves ovarian function and follicular quality by regulating cellular functions and inflammatory pathways, suggesting a novel therapeutic approach for POI.

acupuncture↗