Search

Dysregulation of long non-coding RNAs (lncRNAs) and interferon signaling contributes to tumorigenesis and progression; however, their crosstalk in tumor biology remains poorly understood. Here, we showed that TSPEAR-AS2, an lncRNA mediated by METTL1, activates the interferon signaling pathway in esophageal cancer (ESCA). Clinically, we conducted a pan-cancer investigation and identified TSPEAR-AS2 as a novel ESCA-related lncRNA that predicts a worse patient prognosis. The high expression of TSPEAR-AS2 was validated in multiple ESCA cohorts, demonstrating that this lncRNA had good diagnostic performance. METTL1, an RNA N7-methylguanosine (m7G) methyltransferase, was positively correlated with TSPEAR-AS2 expression in ESCA tissues, and METTL1 was found to induce TSPEAR-AS2 expression in ESCA cells. Functionally, the up-regulation of TSPEAR-AS2 promoted proliferation, cell cycle progression, migration, and stemness in ESCA cells, whereas its knockdown attenuated these malignant phenotypes. Furthermore, both TSPEAR-AS2 deficiency and antisense oligonucleotide (ASO)-based intratumoral intervention could significantly suppress tumor growth in vivo. Mechanistically, quantitative proteomic analysis revealed that TSPEAR-AS2 ablation altered the expression of functional proteins related to interferon signaling pathways, such as HLA-E, IRF3, and IFITs. These findings identify a previously unrecognized role of the METTL1/TSPEAR-AS2/interferon signaling axis in ESCA development and suggest that TSPEAR-AS2 is a potential prognostic indicator and therapeutic vulnerability for this malignancy. [ABSTRACT FROM AUTHOR]

As the global population of older persons increases, age-related medical conditions will have a greater impact on public health. DXA-derived bone and soft tissue metrics are associated with adverse clinical events in aging persons. This study aims to investigate the regional body composition of the appendices by whole-body DXA scans, and the age-related relationships between measures of bone and soft tissue in healthy Caucasian females of a Greek origin residing in the Mediterranean area. Body composition of the legs and the arms was analyzed, and lean mass (LM) and fat mass (FM) metrics were calculated in 330 women aged 20–85 years, using DXA. Peak bone mineral density (BMD) of the legs and arms was achieved between ages 20–30 and 41–50 years, respectively. The overall BMD reduction with age was for the legs 43% and the arms 32.2% (p < 0.001). Peak %LM of the legs and the arms was achieved between ages 20–30. The overall reduction of %LM with age was for the legs 22.5% (p < 0.001) and arms 6.6% (p < 0.05). Peak %FM of the legs and arms was attained between ages 31–40 and 61–70, respectively. The overall %FM reduction with age was for the legs and arms 7.5% and 1.9% (p > 0.05). In appendicular sites, Greek women reach peak values of bone mass in the legs first, in early adulthood. Bone loss predominates in the legs as women age. Also, with advancing age Greek women show preferential significant decreases of %LM and %FM in the legs as opposed to the arms. Although variation in appendicular bone and soft tissue metrics is present, the implications of variable biological crosstalks among the tissue components as women age may ultimately lay the foundation for future clinical trials aimed at healthy aging. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) is a prevalent malignancy with complex heterogeneity within epithelial cells, which plays a crucial role in tumor progression and immune regulation. Yet, the clinical importance of the malignant epithelial cell-related genes (MECRGs) in ccRCC remains insufficiently understood. This research aims to undertake a comprehensive investigation into the functions and clinical relevance of malignant epithelial cell-related genes in ccRCC, providing valuable understanding of the molecular mechanisms and offering potential targets for treatment strategies. Using data from single-cell sequencing, we successfully identified 219 MECRGs and established a prognostic model MECRGS (MECRGs' signature) by synergistically analyzing 101 machine-learning models using 10 different algorithms. Remarkably, the MECRGS demonstrated superior predictive performance compared to traditional clinical features and 92 previously published signatures across six cohorts, showcasing its independence and accuracy. Upon stratifying patients into high- and low-MECRGS subgroups using the specified cut-off threshold, we noted that patients with elevated MECRGS scores displayed characteristics of an immune suppressive tumor microenvironment (TME) and showed worse outcomes after immunotherapy. Additionally, we discovered a distinct ccRCC tumor cell subtype characterized by the high expressions of PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) and SAA1 (Serum Amyloid A1), which we further validated in the Renji tissue microarray (TMA) cohort. Lastly, 'Cellchat' revealed potential crosstalk patterns between these cells and other cell types, indicating their potential role in recruiting CD163 + macrophages and regulatory T cells (Tregs), thereby establishing an immunosuppressive TME. PLOD2 + SAA1 + cancer cells with intricate crosstalk patterns indeed show promise for potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

The activation of spinal astrocytes accounts for opioid-induced hyperalgesia (OIH), but the underlying mechanisms remain elusive. The presence of astrocyte-neuron lactate shuttle (ANLS) makes astrocytes necessary for some neural function and communication. The aim of this study was to explore the role of ANLS in the occurrence and maintenance of OIH. After 7 days consecutive morphine injection, a mice OIH model was established and astrocytic pyruvate dehydrogenase kinase 4 (PDK4), phosphorylated pyruvate dehydrogenase (p-PDH) and accumulation of L-lactate was elevated in the spinal dorsal horn. Intrathecally administration of inhibitors of PDK, lactate dehydrogenase 5 and monocarboxylate transporters to decrease the supply of L-lactate on neurons was observed to attenuate hypersensitivity behaviors induced by repeated morphine administration and downregulate the expression of markers of central sensitization in the spinal dorsal horns. The astrocyte line and the neuronal line were co-cultured to investigate the mechanisms in vitro. In this study, we demonstrated that morphine-induced hyperalgesia was sustained by lactate overload consequent upon aberrant function of spinal ANLS. In this process, PDK-p-PDH-lactate axis serves a pivotal role, which might therefore be a new target to improve long-term opioid treatment strategy in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Metabolic reprogramming and abnormal glucose metabolism are hallmarks of head and neck squamous cell carcinoma (HNSCC). Certain oncogenes can promote cancer‐related metabolic changes, but understanding their crosstalk in HNSCC biology and treatment is essential for identifying predictive biomarkers and developing target therapies. Methods: We assessed the value of survivin/BIRC5 as a radioresistance factor potentially modulated by glucose for predicting therapeutic sensitivity and prognosis of HNSCC in a cohort of 32 patients. Additionally, we conducted in vitro experiments to explore the role of survivin/BIRC5 in glucose metabolism concerning radiation response. Results: Tumoral BIRC5 expression is associated with serum glucose and predicts locoregional disease‐free survival and lower BIRC5 mRNA levels are associated with better outcomes. Upregulation of BIRC5 by radiation depends on glucose levels and provokes a pro‐tumoral and radioresistant phenotype in surviving cells. Conclusions: Survivin/BIRC5 might be independently associated with the risk of recurrence in patients with HNSCC. [ABSTRACT FROM AUTHOR]

The liver is a crucial organ in the regulation of metabolism, signaling, and homeostasis. Using recent advanced sequencing technologies, several mutations of genes in major metabolic and signaling pathways have been discovered in the pathogenesis of hepatocellular carcinoma (HCC). These gene signatures alter expression and ultimately affect biochemical pathways by modifying enzyme/protein levels, resulting in numerous clinical outcomes related to HCC. It comes with varying forms of genetic and biochemical alterations, associated with carbohydrate, lipid, nucleic acid, and amino acid metabolism, as well as signaling pathways linked to tumorigenesis. Here, we aim to summarize the main components and mechanisms involved in the progression of HCC with a special focus on the metabolic regulation of key effectors of tumorigenesis, through the crosstalk between genetics and biochemistry. This paper provides an overview of hepatocellular carcinoma, underlying the fundamental effect of gene variations on metabolic and signaling pathways. Since there is still an unmet need for biomarkers and novel therapeutic targets, some of these signature genes or proteins can be used as novel biomarkers for diagnosis, prognosis, and novel potential therapeutic targets for the treatment of HCC. [ABSTRACT FROM AUTHOR]

The link between ferroptosis, a form of cell death mediated by iron and acute kidney injury (AKI) is recently gaining widespread attention. However, the mechanism of the crosstalk between cells in the pathogenesis and progression of acute kidney injury remains unexplored. In our research, we performed a non-negative matrix decomposition (NMF) algorithm on acute kidney injury single-cell RNA sequencing data based specifically focusing in ferroptosis-associated genes. Through a combination with pseudo-time analysis, cell–cell interaction analysis and SCENIC analysis, we discovered that proximal tubular cells, macrophages, and fibroblasts all showed associations with ferroptosis in different pathways and at various time. This involvement influenced cellular functions, enhancing cellular communication and activating multiple transcription factors. In addition, analyzing bulk expression profiles and marker genes of newly defined ferroptosis subtypes of cells, we have identified crucial cell subtypes, including Egr1 + PTC-C1, Jun + PTC-C3, Cxcl2 + Mac-C1 and Egr1 + Fib-C1. All these subtypes which were found in AKI mice kidneys and played significantly distinct roles from those of normal mice. Moreover, we verified the differential expression of Egr1, Jun, and Cxcl2 in the IRI mouse model and acute kidney injury human samples. Finally, our research presented a novel analysis of the crosstalk of proximal tubular cells, macrophages and fibroblasts in acute kidney injury targeting ferroptosis, therefore, contributing to better understanding the acute kidney injury pathogenesis, self-repairment and acute kidney injury-chronic kidney disease (AKI-CKD) progression. [ABSTRACT FROM AUTHOR]

Introduction: Cross‐talk among biological pathways is essential for normal biological function and plays a significant role in cancer progression. Through integrated network analysis, this study explores the significance of pathway cross‐talk in colorectal cancer (CRC) development at both the pathway and gene levels. Methods: In this study, we integrated the gene expression data with domain knowledge to construct state‐dependent pathway cross‐talk networks. The significance of the genes involved in pathway cross‐talk was assessed by analyzing their association with cancer hallmarks, disease‐gene relation, genetic alterations, and survival analysis. We also analyzed the gene regulatory network to identify the dysregulated genes and their role in CRC progression. Results: Cross‐talk was observed between immune‐related pathways and pathways associated with cell communication and signaling. The PTPRC gene was identified as a mediator, facilitating interactions within the immune system and other signaling pathways. The rewired interactions of ITGA7 were identified as influential in the epithelial‐mesenchymal transition in CRC. This study also highlighted the crucial link between cell communication and vascular smooth muscle contraction pathway in CRC progression. The survival analysis of identified gene clusters showed their significant prognostic value in distinguishing high‐risk from low‐risk CRC groups, and L1000CDS2 revealed seven potential drug molecules in CRC. Nine dysregulated genes (CTNNB1, EP300, JUN, MYC, NFKB1, RELA, SP1, STAT1, and TP53) emerge as transcription factors acting as common regulators across various pathways. Conclusions: This study highlights the crucial role of pathway cross‐talk in CRC progression and identified the potential prognostic biomarkers and potential drug molecules. [ABSTRACT FROM AUTHOR]

Nuclear factor κ-B (NFκB) is activated in iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) under basal conditions, and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single-cell RNA-Seq to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA-Seq and cellular indexing of transcriptomes and epitomes (CITE-Seq) studies revealed marked proinflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts, and CCR2+ macrophages. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were dependent on CCR2+ macrophage recruitment to the heart. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM. [ABSTRACT FROM AUTHOR]

Motivation Multi-omics data provide a comprehensive view of gene regulation at multiple levels, which is helpful in achieving accurate diagnosis of complex diseases like cancer. However, conventional integration methods rarely utilize prior biological knowledge and lack interpretability. Results To integrate various multi-omics data of tissue and liquid biopsies for disease diagnosis and prognosis, we developed a biological pathway informed Transformer, Pathformer. It embeds multi-omics input with a compacted multi-modal vector and a pathway-based sparse neural network. Pathformer also leverages criss-cross attention mechanism to capture the crosstalk between different pathways and modalities. We first benchmarked Pathformer with 18 comparable methods on multiple cancer datasets, where Pathformer outperformed all the other methods, with an average improvement of 6.3%–14.7% in F1 score for cancer survival prediction, 5.1%–12% for cancer stage prediction, and 8.1%–13.6% for cancer drug response prediction. Subsequently, for cancer prognosis prediction based on tissue multi-omics data, we used a case study to demonstrate the biological interpretability of Pathformer by identifying key pathways and their biological crosstalk. Then, for cancer early diagnosis based on liquid biopsy data, we used plasma and platelet datasets to demonstrate Pathformer's potential of clinical applications in cancer screening. Moreover, we revealed deregulation of interesting pathways (e.g. scavenger receptor pathway) and their crosstalk in cancer patients' blood, providing potential candidate targets for cancer microenvironment study. Availability and implementation Pathformer is implemented and freely available at https://github.com/lulab/Pathformer. [ABSTRACT FROM AUTHOR]

Background: Mucinous colorectal adenocarcinoma (MCA) is a distinct subtype of colorectal cancer (CRC) with the most aggressive pattern, but effective treatment of MCA remains a challenge due to its vague pathological characteristics. An in‐depth understanding of transcriptional dynamics at the cellular level is critical for developing specialised MCA treatment strategies. Methods: We integrated single‐cell RNA sequencing and spatial transcriptomics data to systematically profile the MCA tumor microenvironment (TME), particularly the interactome of stromal and immune cells. In addition, a three‐dimensional bioprinting technique, canonical ex vivo co‐culture system, and immunofluorescence staining were further applied to validate the cellular communication networks within the TME. Results: This study identified the crucial intercellular interactions that engaged in MCA pathogenesis. We found the increased infiltration of FGF7+/THBS1+ myofibroblasts in MCA tissues with decreased expression of genes associated with leukocyte‐mediated immunity and T cell activation, suggesting a crucial role of these cells in regulating the immunosuppressive TME. In addition, MS4A4A+ macrophages that exhibit M2‐phenotype were enriched in the tumoral niche and high expression of MS4A4A+ was associated with poor prognosis in the cohort data. The ligand‐receptor‐based intercellular communication analysis revealed the tight interaction of MUC1+ malignant cells and ZEB1+ endothelial cells, providing mechanistic information for MCA angiogenesis and molecular targets for subsequent translational applications. Conclusions: Our study provides novel insights into communications among tumour cells with stromal and immune cells that are significantly enriched in the TME during MCA progression, presenting potential prognostic biomarkers and therapeutic strategies for MCA. Key points: Tumour microenvironment profiling of MCA is developed.MUC1+ tumour cells interplay with FGF7+/THBS1+ myofibroblasts to promote MCA development.MS4A4A+ macrophages exhibit M2 phenotype in MCA.ZEB1+ endotheliocytes engage in EndMT process in MCA. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is an immune-mediated disorder influenced by environmental factors on a genetic basis. Despite advancements, challenges persist, including the diminishing efficacy of biologics and small-molecule targeted agents, alongside managing recurrence and psoriasis-related comorbidities. Unraveling the underlying pathogenesis and identifying valuable biomarkers remain pivotal for diagnosing and treating psoriasis. Methods: We employed a series of bioinformatics (including single-cell sequencing data analysis and machine learning techniques) and statistical methods to integrate and analyze multi-level data. We observed the cellular changes in psoriatic skin tissues, screened the key genes Fatty acid binding protein 5 (FABP5) and The killer cell lectin-like receptor B1 (KLRB1), evaluated the efficacy of six widely prescribed drugs on psoriasis treatment in modulating the dendritic cell-associated pathway, and assessed their overall efficacy. Finally, RT-qPCR, immunohistochemistry, and immunofluorescence assays were used to validate. Results: The regulatory influence of dendritic cells (DCs) on T cells through the CD70/CD27 signaling pathway may emerge as a significant facet of the inflammatory response in psoriasis. Notably, FABP5 and KLRB1 exhibited upregulation and co-localization in psoriatic skin tissues and M5-induced HaCaT cells, serving as potential biomarkers influencing psoriasis development. Conclusion: Our study analyzed the impact of DC-T cell crosstalk in psoriasis, elucidated the characterization of two biomarkers, FABP5 and KLRB1, in psoriasis, and highlighted the promise and value of tofacitinib in psoriasis therapy targeting DCs. [ABSTRACT FROM AUTHOR]

Background: A complex interrelationship exists between Heart Failure (HF) and chronic kidney disease (CKD). This study aims to clarify the molecular mechanisms of the organ-to-organ interplay between heart failure and CKD, as well as to identify extremely sensitive and specific biomarkers. Methods: Differentially expressed tandem genes were identified from HF and CKD microarray datasets and enrichment analyses of tandem perturbation genes were performed to determine their biological functions. Machine learning algorithms are utilized to identify diagnostic biomarkers and evaluate the model by ROC curves. RT-PCR was employed to validate the accuracy of diagnostic biomarkers. Molecular subtypes were identified based on tandem gene expression profiling, and immune cell infiltration of different subtypes was examined. Finally, the ssGSEA score was used to build the ImmuneScore model and to assess the differentiation between subtypes using ROC curves. Results: Thirty-three crosstalk genes were associated with inflammatory, immune and metabolism-related signaling pathways. The machine-learning algorithm identified 5 hub genes (PHLDA1, ATP1A1, IFIT2, HLTF, and MPP3) as the optimal shared diagnostic biomarkers. The expression levels of tandem genes were negatively correlated with left ventricular ejection fraction and glomerular filtration rate. The CIBERSORT results indicated the presence of severe immune dysregulation in patients with HF and CKD, which was further validated at the single-cell level. Consensus clustering classified HF and CKD patients into immune and metabolic subtypes. Twelve immune genes associated with immune subtypes were screened based on WGCNA analysis, and an ImmuneScore model was constructed for high and low risk. The model accurately predicted different molecular subtypes of HF or CKD. Conclusion: Five crosstalk genes may serve as potential biomarkers for diagnosing HF and CKD and are involved in disease progression. Metabolite disorders causing activation of a large number of immune cells explain the common pathogenesis of HF and CKD. [ABSTRACT FROM AUTHOR]

Patients with cirrhosis have intestinal barrier dysfunction but the role of the individual cell types in human small intestine is unclear. We performed single-nuclear RNA sequencing (snRNAseq) in the pinch biopsies of terminal ileum of four age-matched men [56 years, healthy control, compensated, early (ascites and lactulose use) and advanced decompensated cirrhosis (ascites and rifaximin use)]. Cell type proportions, differential gene expressions, cell-type specific pathway analysis using IPA, and cellular crosstalk dynamics were compared. Stem cells, enterocytes and Paneth cells were lowest in advanced decompensation. Immune cells like naive CD4 + T cells were lowest while ITGAE + cells were highest in advanced decompensation patients. MECOM had lowest expression in stem cells in advanced decompensation. Defensin and mucin sulfation gene (PAPSS2) which can stabilize the mucus barrier expression were lowest while IL1, IL6 and TNF-related genes were significantly upregulated in the enterocytes, goblet, and Paneth cells in decompensated subjects. IPA analysis showed higher inflammatory pathways in enterocytes, stem, goblet, and Paneth cells in decompensated patients. Cellular crosstalk analysis showed that desmosome, protease-activated receptors, and cadherin-catenin complex interactions were most perturbed in decompensated patients. In summary, the snRNAseq of the human terminal ileum in 4 subjects (1 control and three cirrhosis) identified multidimensional alteration in the intestinal barrier with lower stem cells and altered gene expression focused on inflammation, mucin sulfation and cell–cell interactions with cirrhosis decompensation. [ABSTRACT FROM AUTHOR]

This review article will focus on subpopulations of fibroblasts that get reprogrammed by tumor cells into cancer-associated fibroblasts. Throughout this article, we will discuss the intricate interactions between fibroblasts, immune cells, and tumor cells. Unravelling complex intercellular crosstalk will pave the way for new insights into cellular mechanisms underlying the reprogramming of the local tumor immune microenvironment and propose novel immunotherapy strategies that might have potential in harnessing and modulating immune system responses. [ABSTRACT FROM AUTHOR]

Macrophages polarized into distinct phenotypes play vital roles in inflammatory diseases by clearing pathogens, promoting tissue repair, and maintaining homeostasis. Metabolism serves as a fundamental driver in regulating macrophage polarization, and understanding the interplay between macrophage metabolism and polarization is crucial for unraveling the mechanisms underlying inflammatory diseases. The intricate network of cellular signaling pathway plays a pivotal role in modulating macrophage metabolism, and growing evidence indicates that the Hippo pathway emerges as a central player in network of cellular metabolism signaling. This review aims to explore the impact of macrophage metabolism on polarization and summarize the cell signaling pathways that regulate macrophage metabolism in diseases. Specifically, we highlight the pivotal role of the Hippo pathway as a key regulator of cellular metabolism and reveal its potential relationship with metabolism in macrophage polarization. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic steatohepatitis (NASH) is a progressive manifestation of nonalcoholic fatty liver disease (NAFLD) that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Despite the growing knowledge of NASH and HCC, the association between the two conditions remains to be fully explored. Bioinformatics has emerged as a valuable approach for identifying disease-specific feature genes, enabling advancements in disease prediction, prevention, and personalized treatment strategies. Materials and methods: In this study, we utilized CellChat, copy number karyotyping of aneuploid tumors (CopyKAT), consensus Non-negative Matrix factorization (cNMF), Gene set enrichment analysis (GSEA), Gene set variation analysis (GSVA), Monocle, spatial co-localization, single sample gene set enrichment analysis (ssGSEA), Slingshot, and the Scissor algorithm to analyze the cellular and immune landscape of NASH and HCC. Through the Scissor algorithm, we identified three cell types correlating with disease phenotypic features and subsequently developed a novel clinical prediction model using univariate, LASSO, and multifactor Cox regression. Results: Our results revealed that macrophages are a significant pathological factor in the development of NASH and HCC and that the macrophage migration inhibitory factor (MIF) signaling pathway plays a crucial role in cellular crosstalk at the molecular level. We deduced three prognostic genes (YBX1, MED8, and KPNA2), demonstrating a strong diagnostic capability in both NASH and HCC. Conclusion: These findings shed light on the pathological mechanisms shared between NASH and HCC, providing valuable insights for the development of novel clinical strategies. [ABSTRACT FROM AUTHOR]

Metabolic plasticity enables cancer cells to meet divergent demands for tumorigenesis, metastasis and drug resistance. Landscape analysis of tumor metabolic plasticity spanning different cancer types, in particular, metabolic crosstalk within cell subpopulations, remains scarce. Therefore, we proposed a new in-silico framework, termed as MMP3C (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to depict tumor metabolic plasticity based on transcriptome data. Next, we performed an extensive metabo-plastic analysis of over 6000 tumors comprising 13 cancer types. The metabolic plasticity within distinct cell subpopulations, particularly interplay with tumor microenvironment, were explored at single-cell resolution. Ultimately, the metabo-plastic events were screened out for multiple clinical applications via machine learning methods. The pilot research indicated that 6 out of 13 cancer types exhibited signs of the Warburg effect, implying its high reliability and robustness. Across 13 cancer types, high metabolic organized heterogeneity was found, and four metabo-plastic subtypes were determined, which link to distinct immune and metabolism patterns impacting prognosis. Moreover, MMP3C analysis of approximately 60 000 single cells of eight breast cancer patients unveiled several metabo-plastic events correlated to tumorigenesis, metastasis and immunosuppression. Notably, the metabolic features screened out by MMP3C are potential biomarkers for diagnosis, tumor classification and prognosis. MMP3C is a practical cross-platform tool to capture tumor metabolic plasticity, and our study unveiled a core set of metabo-plastic pairs among diverse cancer types, which provides bases toward improving response and overcoming resistance in cancer therapy. [ABSTRACT FROM AUTHOR]

Heavy metal (HM) stress poses a global risk to crops, ecological systems, and human health. It disrupts cellular ionic equilibrium, cell membrane integrity, metabolic balance, and the activities of enzymes and proteins, severely impacting physiological processes, plant development, and agricultural productivity. Although plants naturally activate defense mechanisms to mitigate the adverse effects of HM stress, they cannot completely prevent them. Phytohormones counter HM toxicity, aiding growth. External application and internal regulation via signaling/biosynthesis genes offer defense against HM-induced damage. A pivotal signaling molecule in plant adaptive responses to environmental stressors, including HM toxicity, is abscisic acid (ABA). Despite ABA's role in abiotic stress responses such as drought and salinity, its function and crosstalk with other phytohormones under HM stress remain poorly understood. Nonetheless, exogenously applied ABA serves as a strategic approach to enhancing plants' resistance to HM toxicity by promoting osmolyte accumulation and reinforcing antioxidant activity. ABA significantly regulates various plant growth and metabolic activities under diverse environmental conditions. This review highlights the effects of HM stress on plants and explores ABA involvement in production, signaling, catabolism, and transport within plant tissues. The purpose of this paper is to shed light on the complex interplay between the metabolism of ABA, its signaling, and its interactions with other phytohormones (e.g., auxins, gibberellins, and ethylene) during HM exposure. Furthermore, we delve into the function of ABA to mitigate HM stress and elucidate its interactions with other phytohormones. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by limited responses to chemoimmunotherapy attributed to highly desmoplastic tumor microenvironment. Disrupting the tumor-stromal cell crosstalk is considered as an improved PDAC treatment strategy, whereas little progress has been made due to poor understanding of its underlying mechanism. Here, we examined the cellular role of melanoma associated antigen A isoforms (MAGEA) in regulating tumor-stromal crosstalk mediated chemoresistance. Methods: We used clinical samples to explore the correlation between MAGEA expression and patient prognosis in multiple cancers. We utilized cancer cell lines, patient derived organoids and orthotopic PDAC model to examine the function of MAGEA in chemoresistance. We performed biochemical, proteome profiler array and transcriptional analysis to uncover a mechanism that governs tumor-stromal crosstalk. We developed a multi-MAGEA antigen targeted DNA vaccine and tested its effect on PDAC tumor growth. Results: We establish MAGEA as a regulator of the tumor-stromal crosstalk in PDAC. We provide strong clinical evidence indicating that high MAGEA expression, including MAGEA2, MAGEA3 and MAGEA10, correlates with worse chemotherapeutic response and poor prognosis in multiple cancers, while their expression is up-regulated in chemoresistant PDAC patient derived organoids and cancer cell lines. Mechanistically, MAGEA2 prohibits gemcitabine-induced JNK-c-Jun-p53 mediated cancer cell apoptosis, while gemcitabine stimulated pancreatic stellate cells secretes GDF15 to further enhance the gemcitabine resistance of MAGEA2 expressing cells by activating GFRAL-RET mediated Akt and ERK1/2 dependent survival pathway. Strikingly, immunization with a DNA vaccine that targeting multiple MAGEA antigens, including MAGEA2, MAGEA3 and MAGEA10, elicits robust immune responses against the growth of gemcitabine resistant tumors. Conclusions: These findings suggest that targeting MAGEA-mediated paracrine regulation of chemoresistance by immunotherapy can be an improved pancreatic cancer treatment strategy. [ABSTRACT FROM AUTHOR]

Epithelial-mesenchymal transition (EMT) is a cellular reprogramming process that converts epithelial cells into mesenchymal-like cells with migratory and invasive capabilities. The initiation and regulation of EMT is closely linked to a range of transcription factors, cell adhesion molecules and signaling pathways, which play a key role in cancer metastasis and drug resistance. The regulation of ferroptosis is intricately linked to various cell death pathways, intracellular iron homeostasis, and the protein network governing iron supply and storage. The ability of ferroptosis to disrupt cancer cells and overcome drug resistance lies in its control of intracellular iron ion levels. EMT process can promote the accumulation of iron ions, providing conditions for ferroptosis. Conversely, ferroptosis may impact the regulatory network of EMT by modulating transcription factors, signaling pathways, and cell adhesion molecules. Thus, ferroptosis related genes and signaling pathways and oxidative homeostasis play important roles in the regulation of EMT. In this paper, we review the role of ferroptosis related genes and their signaling pathways in regulating cancer EMT to better understand the crosstalk mechanism between ferroptosis and EMT, aiming to provide better therapeutic strategies for eradicating cancer cells and overcoming drug resistance. [ABSTRACT FROM AUTHOR]

Cell-to-cell variability during TNFα stimulated Tumor Necrosis Factor Receptor 1 (TNFR1) signaling can lead to single-cell level pro-survival and apoptotic responses. This variability stems from the heterogeneity in signal flow through intracellular signaling entities that regulate the balance between these two phenotypes. Using systematic Boolean dynamic modeling of a TNFR1 signaling network, we demonstrate that the signal flow path variability can be modulated to enable cells favour apoptosis. We developed a computationally efficient approach "Boolean Modeling based Prediction of Steady-state probability of Phenotype Reachability (BM-ProSPR)" to accurately predict the network's ability to settle into different phenotypes. Model analysis juxtaposed with the experimental observations revealed that NFκB and PI3K transient responses guide the XIAP behaviour to coordinate the crucial dynamic cross-talk between the pro-survival and apoptotic arms at the single-cell level. Model predicted the experimental observations that ~31% apoptosis increase can be achieved by arresting Comp1 – IKK* activity which regulates the NFκB and PI3K dynamics. Arresting Comp1 – IKK* activity causes signal flow path re-wiring towards apoptosis without significantly compromising NFκB levels, which govern adequate cell survival. Priming an ensemble of cancerous cells with inhibitors targeting the specific interaction involving Comp1 and IKK* prior to TNFα exposure could enable driving them towards apoptosis. [ABSTRACT FROM AUTHOR]

Spermatogenesis is supported by various posttranslational modifications. There is growing evidence supporting a crosstalk between sumoylation and phosphorylation in different cell types. We have recently shown that inhibition of global sumoylation with a sumoylation inhibitor (Ginkgolic acid, GA) arrested purified mouse spermatocytes in vitro ; the spermatocytes could not condense chromatin and disassemble the synaptonemal complex. Our data have also revealed that some kinases regulating the meiotic prophase (PLK1 and AURKB) were inhibited upon the inhibition of sumoylation. Nevertheless, specific phosphorylated targets affected by the inhibition of sumoylation have not been identified. To address this gap, in this study, we performed a comparative phospho-proteome analysis of the control spermatocytes and spermatocytes treated with the GA. Our analysis has narrowed down to several proteins implicated in the regulation of cell cycle and/or meiosis. Two of these targets, NPM1 and hnRNPH1, were studied further using western blotting in both cell lines and primary cells. Decrease in sumoylaion-dependend phosphorylation of NPM1 on Ser125 regulated by AURKB can be a contributing factor to the inability of spermatocytes to condense chromatin by the end of the prophase and should be studied further. • Downregulation of sumoylation causes changes in phosphorylation of important spermatocyte proteins. • Sumoylation regulates NPM1 in GC-1 spermatogonia and mouse spermatocytes. • Sumoylation regulates hnRNPH1 in GC-1 spermatogonia mouse spermatocytes. • Phosphorylation of NPM1 on Ser125 regulated by AURKB should be studied further. [ABSTRACT FROM AUTHOR]

As central nervous system (CNS)-related disorders present an increasing cause of global morbidity, mortality, and high pressure on our healthcare system, there is an urgent need for new insights and treatment options. The endocannabinoid system (ECS) is a critical network of endogenous compounds, receptors, and enzymes that contribute to CNS development and regulation. Given its multifaceted involvement in neurobiology and its significance in various CNS disorders, the ECS as a whole is considered a promising therapeutic target. Despite significant advances in our understanding of the ECS's role in the CNS, its complex architecture and extensive crosstalk with other biological systems present challenges for research and clinical advancements. To bridge these knowledge gaps and unlock the full therapeutic potential of ECS interventions in CNS-related disorders, a plethora of molecular–genetic tools have been developed in recent years. Here, we review some of the most impactful tools for investigating the neurological aspects of the ECS. We first provide a brief introduction to the ECS components, including cannabinoid receptors, endocannabinoids, and metabolic enzymes, emphasizing their complexity. This is followed by an exploration of cutting-edge imaging tools and genetic models aimed at elucidating the roles of these principal ECS components. Special emphasis is placed on their relevance in the context of CNS and its associated disorders. [ABSTRACT FROM AUTHOR]

Kupffer cells (KCs) are liver‐resident macrophages involved in hepatic inflammatory responses, including nonalcoholic fatty liver disease (NAFLD) development. However, the contribution of KC subsets to liver inflammation remains unclear. Here, using high‐dimensional single‐cell RNA sequencing, we characterized murine embryo‐derived KCs and identified two KC populations with different gene expression profiles: KC‐1 and KC‐2. KC‐1 expressed CD170, exhibiting immunoreactivity and immune‐regulatory abilities, while KC‐2 highly expressed lipid metabolism‐associated genes. In a high‐fat diet–induced NAFLD model, KC‐1 cells differentiated into pro‐inflammatory phenotypes and initiated more frequent communications with invariant natural killer T (iNKT) cells. In KC‐1, interleukin (IL)‐10 expression was unaffected by the high‐fat diet but impaired by iNKT cell ablation and upregulated by iNKT cell adoptive transfer in vivo. Moreover, in a cellular co‐culture system, primary hepatic iNKT cells promoted IL‐10 expression in RAW264.7 and primary KC‐1 cells. CD206 signal blocking in KC‐1 or CD206 knockdown in RAW264.7 cells significantly reduced IL‐10 expression. In conclusion, we identified two embryo‐derived KC subpopulations with distinct transcriptional profiles. The CD206‐mediated crosstalk between iNKT and KC‐1 cells maintains IL‐10 expression in KC‐1 cells, affecting hepatic immune balance. Therefore, KC‐based therapeutic strategies must consider cellular heterogeneity and the local immune microenvironment for enhanced specificity and efficiency. [ABSTRACT FROM AUTHOR]

Background: Important roles of INHBB in various malignancies are increasingly identified. The underlying mechanisms in gastric cancer (GC) microenvironment are still greatly unexplored. Methods: The clinical significance of INHBB and the correlation between INHBB and p-p65 in GC were assessed through analyzing publicly available databases and human paraffin embedded GC tissues. The biological crosstalk of INHBB between GC cells and fibroblasts was explored both in vitro and in vivo. RNA-seq analyses were performed to determine the mechanisms which regulating fibroblasts reprogramming. Luciferase reporter assay and chromatin immunoprecipitation (CHIP) assay were used to verify the binding relationship of p65 and INHBB in GC cells. Results: Our study showed that INHBB level was significantly higher in GC, and that increased INHBB was associated with poor survival. INHBB positively regulates the proliferation, migration, and invasion of GC cells in vitro. Also, activin B promotes the occurrence of GC by reprogramming fibroblasts into cancer-associated fibroblasts (CAFs). The high expression of INHBB in GC cells activates the NF-κB pathway of normal gastric fibroblasts by secreting activin B, and promotes fibroblasts proliferation, migration, and invasion. In addition, activin B activates NF-κB pathway by controlling TRAF6 autoubiquitination to induce TAK1 phosphorylation in fibroblasts. Fibroblasts activated by activin B can induce the activation of p65 phosphorylation of GC cells by releasing pro-inflammatory factors IL-1β. p65 can directly bind to the INHBB promoter and increase the INHBB transcription of GC cells, thus establishing a positive regulatory feedback loop to promote the progression of GC. Conclusions: GC cells p65/INHBB/activin B and fibroblasts p65/IL-1β signal loop led to the formation of a whole tumor-promoting inflammatory microenvironment, which might be a promising therapeutic target for GC. Highlights: Tumor-secreted activin B promotes gastric cancer via fibroblast reprogramming. Activin B activates the NF-κB pathway by inducing auto-ubiquitination of TRAF6 in fibroblasts. Activin B stimulates the production of a pro-tumorigenic secretome and matrisome. Activin B activates NF-κB pathway of fibroblasts to up-regulate IL-1β secretion. IL-1β activates transcription factor p65 of gastric cancer to up-regulate INHBB expression. [ABSTRACT FROM AUTHOR]

Background: Periodontits (PD) and Alzheimer’s disease (AD) are both associated with ageing and clinical studies increasingly evidence their association. However, specific mechanisms underlying this association remain undeciphered, and immune-related processes are purported to play a signifcant role. The accrual of publicly available transcriptomic datasets permits secondary analysis and the application of data-mining and bioinformatic tools for biological discovery. Aim: The present study aimed to leverage publicly available transcriptomic datasets and databases, and apply a series of bioinformatic analysis to identify a robust signature of immune-related signature of PD and AD linkage. Methods: We downloaded gene-expresssion data pertaining PD and AD and identified crosstalk genes. We constructed a protein-protein network analysis, applied immune cell enrichment analysis, and predicted crosstalk immune-related genes and infiltrating immune cells. Next, we applied consisent cluster analysis and performed immune cell bias analysis, followed by LASSO regression to select biomarker immune-related genes. Results: The results showed a 3 gene set comprising of DUSP14, F13A1 and SELE as a robust immune-related signature. Macrophages M2 and NKT, B-cells, CD4+ memory T-cells and CD8+ naive T-cells emerged as key immune cells linking PD with AD. Conclusion: Candidate immune-related biomarker genes and immune cells central to the assocation of PD with AD were identified, and merit investigation in experimental and clinical research. [ABSTRACT FROM AUTHOR]

Animals models are essential to understand the complex pathobiology of human diseases. George Box's aphorism based on statistics "All models are wrong, but some are useful" certainly applies to animal models of disease. In this session, the translational relevance of various animal models applicable to human liver disease was explored starting with a historic overview of the rodent cancer bioassay with emphasis on hepatocarcinogenesis from early work at the National Cancer Institute, refinement by the National Toxicology Program and contemporary efforts to identify potential mechanisms and their relevance to human cancer risk. Subsequently, recently elucidated understanding of the molecular drivers and signaling mechanisms of liver pathophysiology and liver cancer, including factors associated with liver regeneration, metabolic hepatocellular zonation, and the role of macrophages and their crosstalk with stellate cells in understanding human liver disease was discussed. Next, our contemporary understanding of the role of nuclear receptors in hepatic homeostasis and drug response highlighting nuclear receptor activation and crosstalk in modulating biological responses associated with liver damage and neoplastic response were discussed. Finally, an overview and translational relevance of different drug-induced liver injury (DILI) rodent model systems focused on pathology and mechanisms with commentary on current relevant Food and Drug Administration (FDA) perspective were summarized with closing remarks. [ABSTRACT FROM AUTHOR]

Tendinopathy is one of the most common musculoskeletal disorders with significant repercussions on quality of life and sport activities. Physical exercise (PE) is considered the first‐line approach to treat tendinopathy due renowned mechanobiological effects on tenocytes. Irisin, a recently identified myokine released during PE, has been recognized for several beneficial effects towards muscle, cartilage, bone, and intervertebral disc tissues. The aim of this study was to evaluate the effects of irisin on human primary tenocytes (hTCs) in vitro. Human tendons were harvested from specimens of patients undergoing anterior cruciate ligament reconstruction (n = 4). After isolation and expansion, hTCs were treated with RPMI medium (negative control), interleukin (IL)−1β or tumor necrosis factor‐α (TNF‐α) (positive controls; 10 ng/mL), irisin (5, 10, 25 ng/mL), IL‐1β or TNF‐α pretreatment and subsequent co‐treatment with irisin, pretreatment with irisin and subsequent co‐treatment with IL‐1β or TNF‐α. hTC metabolic activity, proliferation, and nitrite production were evaluated. Detection of unphosphorylated and phosphorylated p38 and ERK was performed. Tissue samples were analyzed by histology and immunohistochemistry to evaluate irisin αVβ5 receptor expression. Irisin significantly increased hTC proliferation and metabolic activity, while reducing the production of nitrites both before and after the addition of IL‐1β and TNF‐α. Interestingly, irisin reduced p‐p38 and pERK levels in inflamed hTCs. The αVβ5 receptor was uniformly expressed on hTC plasma membranes, supporting the potential binding of irisin. This is the first study reporting the capacity of irisin to target hTCs and modulating their response to inflammatory stresses, possibly orchestrating a biological crosstalk between the muscle and tendon. [ABSTRACT FROM AUTHOR]

In the present medicine world antibiotic resistance is one of the key threats to universal health coverage. Researchers continue to work hard to combat this global health concern. Phage therapy, an age-old practice during the early twentieth century, was outshined by the discovery of antibiotics. With the advent of widespread antibiotic resistance, phage therapy has again redeemed itself as a potential alternative owing to its adeptness to target bacteria precisely. Limited side effects, the ability to migrate to different body organs, a distinct mode of action, and proliferation at the infection site, make phages a profitable candidate to replace conventional antibiotics. The progressive outcome of numerous in vitro studies and case reports has validated the clinical efficacy of phage therapy. The bright perspective of using phages to treat bacterial infections has fueled enormous medical research to exploit their potential as therapeutics. The gaps in the information about phages and the lack of consent for clinical trials is major hurdle for consideration of phage therapy. Crafting phage therapy as a reality in medicine requires a coordinated effort from different fraternities. With this review, we aim to emphasize the importance of phage therapy in modern medicine. This review explains their historical journey, basic phage biology, cross-talk with the host immunity, obstacles with phage therapy, and their possible remedies. Comprehensive data on the various significant clinical trials of phage therapy has been presented. We evaluated the efficacy of antibiotics and phage therapy in part and in combination, along with recent progress and future perspectives of phage therapy. [ABSTRACT FROM AUTHOR]

A wealth of knowledge regarding glial cell-mediated neuroinflammation, which contributes to cognitive deficits in Alzheimer's disease (AD) has emerged in recent years. Contactin 1(CNTN1), a member of the cell adhesion molecule and immunoglobulin supergene family, is centrally involved in axonal growth regulation and is also a key player in inflammation-associated disorders. However, whether CNTN1 plays a role in inflammation-related cognitive deficits and how this process is triggered and orchestrated remain to be fully elucidated. In this study, we examined postmortem brains with AD. CNTN1 immunoreactivity was markedly increased, particularly in the CA3 subregion, as compared with non-AD brains. Furthermore, by applying an adeno-associated virus-based approach to overexpress CNTN1 directly via stereotactic injection in mice, we demonstrated that hippocampal CNTN1 overexpression triggered cognitive deficits detected by novel objectrecognition, novel place-recognition and social cognition tests. The mechanisms underlying these cognitive deficits could be attributed to hippocampal microglia and astrocyte activation, which led to aberrant expression of excitatory amino acid transporters (EAAT)1/EAAT2. This resulted in long-term potentiation (LTP) impairment that could be reversed by minocyline, an antibiotic and the best-known inhibitor of microglial activation. Taken together, our results identified Cntn1 as a susceptibility factor involved in regulating cognitive deficits via functional actions in the hippocampus. This factor correlated with microglial activation and triggered astrocyte activation with abnormal EAAT1/EAAT2 expression and LTP impairment. Overall, these findings may significantly advance our understanding of the pathophysiological mechanisms underlying the risk of neuroinflammation related cognitive deficits. [ABSTRACT FROM AUTHOR]

Autosomal recessive (AR) and dominant (AD) deficiencies of TLR3 and TRIF are believed to be crucial genetic causes of herpes simplex encephalitis (HSE), which is a fatal disease causing focal or global cerebral dysfunction following infection with herpes simplex virus type 1 (HSV‐1). However, few studies have been conducted on the immunopathological networks of HSE in the context of TLR3 and TRIF defects at the cellular and molecular levels. In this work, we deciphered the crosstalk between type I IFN (IFN‐I)‐producing epithelial layer and IL‐15‐producing dendritic cells (DC) to activate NK cells for the protective role of TLR3/TRIF pathway in HSE progression after vaginal HSV‐1 infection. TLR3‐ and TRIF‐ablated mice showed enhanced susceptibility to HSE progression, along with high HSV‐1 burden in vaginal tract, lymphoid tissues and CNS. The increased HSV‐1 burden in TLR3‐ and TRIF‐ablated mice did not correlate with increased infiltration of Ly‐6C+ monocytes, but it was closely associated with impaired NK cell activation in vaginal tract. Furthermore, using delicate ex vivo experiments and bone marrow transplantation, TRIF deficiency in tissue‐resident cells, such as epithelial cells in vaginal tract, was found to cause impaired NK cell activation by means of low IFN‐I production, whereas IFN‐I receptor in DC was required for NK cell activation via IL‐15 production in response to IFN‐I produced from epithelial layer. These results provide new information about IFN‐I‐ and IL‐15‐mediated crosstalk between epithelial cells and DC at the primary infection site, which suppresses HSE progression in a TLR3‐ and TRIF‐dependent manner. [ABSTRACT FROM AUTHOR]

There are overwhelming reports on the promotional effect of hypoxia on the malignant behavior of various forms of cancer cells. This has been proposed and tested exhaustively in the light of cancer immunotherapy. However, there could be more interesting functions of a hypoxic cellular micro-environment than malignancy. There is a highly intricate crosstalk between hypoxia inducible factor (HIF), a transcriptional factor produced during hypoxia, and nuclear factor kappa B (NF-kB) which has been well characterized in various immune cell types. This important crosstalk shares common activating and inhibitory stimuli, regulators, and molecular targets. Impaired hydroxylase activity contributes to the activation of HIFs. Inflammatory ligands activate NF-kB activity, which leads to the expression of inflammatory and anti-apoptotic genes. The eventual sequelae of the interaction between these two molecular players in immune cells, either bolstering or abrogating functions, is largely cell-type dependent. Importantly, this holds promise for interesting therapeutic interventions against several infectious diseases, as some HIF agonists have helped prevent immune-related diseases. Hypoxia and inflammation are common features of infectious diseases. Here, we highlighted the role of this crosstalk in the light of functional immunity against infection and inflammation, with special focus on various innate and adaptive immune cells. Particularly, we discussed the bidirectional effects of this crosstalk in the regulation of immune responses by monocytes/macrophages, dendritic cells, neutrophils, B cells, and T cells. We believe an advanced understanding of the interplay between HIFs and NF-kB could reveal novel therapeutic targets for various infectious diseases with limited treatment options. [ABSTRACT FROM AUTHOR]

Sugars and auxin have important effects on almost all phases of plant life cycle, which are so fundamental to plants and regulate similar processes. However, little is known about the effect of cross-talk between glucose and indole-3-acetic acid (IAA) on growth and development of apple trees. To examine the potential roles of glucose and IAA in root architecture, root nitrogen (N) metabolism and photosynthetic capacity in 'Hanfu' (Malus domestica), a total of five treatments was established: single application of glucose, IAA, and auxin polar transport inhibitor (2, 3, 5-triiodobenzoic acid, TIBA), combined application of glucose with TIBA and that of glucose with IAA. The combined application of glucose with IAA improved root topology system and endogenous IAA content by altering the mRNA levels of several genes involved in root growth, auxin transport and biosynthesis. Moreover, the increased N metabolism enzyme activities and levels of genes expression related to N in roots may suggest higher rates of transformation of nitrate (NO3 - -N) into amino acids application of glucose and IAA. Contrarily, single application of TIBA decreased the expression levels of auxin transport gene, hindered root growth and decreased endogenous IAA content. Glucose combined with TIBA application effectively attenuated TIBA-induced reductions in root topology structure, photosynthesis and N metabolism activity, and mRNA expression levels involved in auxin biosynthesis and transport. Taken together, glucose application probably changes the expression level of auxin synthesis and transport genes, and induce the allocation of endogenous IAA in root, and thus improves root architecture and N metabolism of root in soil with deficit carbon. [ABSTRACT FROM AUTHOR]

Acute liver injury (ALI) in children, which commonly leads to acute liver failure (ALF) with the need for liver transplantation, is a devastating life-threatening condition. As the orchestrated regulation of immune hemostasis in the liver is essential for resolving excess inflammation and promoting liver repair in a timely manner, in this study we focused on the immune inflammation and regulation with the functional involvement of both innate and adaptive immune cells in acute liver injury progression. In the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, it was also important to incorporate insights from the immunological perspective for the hepatic involvement with SARS-CoV-2 infection, as well as the acute severe hepatitis of unknown origin in children since it was first reported in March 2022. Furthermore, molecular crosstalk between immune cells concerning the roles of damage-associated molecular patterns (DAMPs) in triggering immune responses through different signaling pathways plays an essential role in the process of liver injury. In addition, we also focused on DAMPs such as high mobility group box 1 (HMGB1) and cold-inducible RNA-binding protein (CIRP), as well as on macrophage mitochondrial DNA-cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) signaling pathway in liver injury. Our review also highlighted novel therapeutic approaches targeting molecular and cellular crosstalk and cell-based therapy, providing a future outlook for the treatment of acute liver injury. [ABSTRACT FROM AUTHOR]

Periodontitis is an inflammatory and immune-related disease with links to several systemic diseases, and the pathological process of atherosclerosis also involves inflammatory and immune involvement. The aim of this study was to investigate the common immune cells and potential crosstalk genes between periodontitis (PD) and atherosclerosis (AS). By analyzing the weighted gene co-expression network of differentially immune infiltrating cells in two diseases to obtain important module genes, and taking the intersection of the module genes, we obtained 14 co-expressed immune-related genes, and evaluated the predictive value of 14 immune-related genes using three machine learning models.Two potential immune-related crosstalk genes (BTK and ITGAL) were finally obtained by taking intersections of WGCNA intersection genes, DEGs and IRGs.Then, the diagnostic column line graphs were constructed based on the 2 crosstalk genes, and the calibration curves, DCA curves and clinical impact curves indicated that the two genes had strong disease prediction ability, and we further validated the accuracy of the two potential crosstalk genes for disease diagnosis in the validation dataset.Single gene GSEA analysis showed that both genes are jointly involved in biological processes such as antigen presentation and immune regulation, and single sample GSEA analysis showed that macrophages and T cells play an important role in periodontitis in atherosclerosis.This study explored the genetic correlation between atherosclerosis and periodontitis using bioinformatics tools. BTK and ITGAL were found to be the most important crosstalk genes between the two diseases and may have an important role in the diagnosis and treatment of the diseases. Macrophage and T cell mediated inflammatory and immune responses may play an important role in periodontitis and atherosclerosis. [ABSTRACT FROM AUTHOR]

Hyperactivation of hypothalamic–pituitary–adrenal (HPA) axis and hypothalamic–pituitary–thyroid (HPT) axis were found in acute high altitude challenge, but the role of gut microbiota and metabolites is unknown. We utilized adult male Sprague–Dawley rats at a simulated altitude of 5500 m for 3 days in a hypobaric-hypoxic chamber. ELISA and metabolomic analyses of serum and 16S rRNA and metabolomic analyses of fecal samples were then performed. Compared with the normoxic group, serum corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT), and thyroxine (tT4) were increased in the hypoxia group, whereas thyrotropin-releasing hormone (TRH) was decreased. Bacteroides, Lactobacillus,Parabacteroides,Butyricimonas,SMB53,Akkermansia,Phascolarctobacterium, and Aerococcus were enriched in hypoxia group, whereas [Prevotella], Prevotella,Kaistobacter,Salinibacterium, and Vogesella were enriched in normoxic group. Metabolomic analysis indicated that acute hypoxia significantly affected fecal and serum lipid metabolism. In addition, we found five fecal metabolites may mediate the cross-talk between TRH, tT4, and CORT with [Prevotella], Kaistobacter,Parabacteroides, and Aerococcus, and 6 serum metabolites may mediate the effect of TRH and tT4 on [Prevotella] and Kaistobacter by causal mediation analysis. In conclusion, this study provides new evidence that key metabolites mediate the cross-talk between gut microbiota with HPA and HPT axis under acute hypobaric hypoxia challenge. [ABSTRACT FROM AUTHOR]

Disabled 1 (Dab1) is an adaptor protein with essential functions regulated by reelin signaling and affects many biological processes in the nervous system, including cell motility, adhesion, cortical development, maturation, and synaptic plasticity. Posttranslational modifications directly guide the fates of cytoplasmic proteins to complete their functions correctly. Reciprocal crosstalk between O-GlcNAcylation and phosphorylation is a dynamic modification in cytoplasmic proteins. It modulates the functions of the proteins by regulating their interactions with other molecules in response to the continuously changeable cell microenvironment. Although Dab1 contains conserved recognition sites for phosphorylation in their N-terminal protein interaction domain, the O-β-GlcNAcylation and phosphorylation sites of human Dab1 sequence, their reciprocal crosstalk, and potential kinases catalyzing the phosphorylation remain unknown. In this study, we determined potential thirty-seven O-β-GlcNAcylation and sixty-seven phosphorylation sites. Conserved twenty-one residues of these glycosylated sites were also phosphorylated with various kinases, including ATM, CKI, DNAPK, GSK3, PKC, PKG, RSK, cdc2, cdk5, and p38MAPK. In addition, we analyzed these conserved sites at our constructed two- and three-dimensional structures of human Dab1 protein. Dab1 protein models were frequently composed of coil structures as well as α-helix and β-strands. Many of these conserved crosstalk sites between O-β-GlcNAcylation and phosphorylation were localized at the coil region of the protein model. These findings may guide biochemical, genetic, and glyco-biology based on further experiments about the Dab1 signaling process. Understanding these modifications might change the point of view of the Dab1 signaling process and treatment for pathological conditions in neurodegenerative diseases such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Chinese medicine is widely applied in Asian and Western countries for its outstanding therapeutic effect, but there are still unsolved problems such as unclear active ingredients and pharmacological effects. The application of nano/microparticle technology in Chinese medicine may become a promising strategy to solve this problem in the near future (provided that more efforts are made to in-depth exploration). In this work, a comprehensive analysis of the field was carried out from a bibliometrics perspective, and further the publishing trends and research hotspots were figured out. Methods: The articles or reviews from 2000 to 2020 were retrieved in the database of Web of Science Core Collection. The documents were processed by Clarivate Analytic, Visualization of Similarities viewer, Statistical Analysis Toolkit for Informetrics and bibliometric online platform, and the data were visualized. Finally, a bibliometric summary, citation analysis results and research trends were described. Results: A bibliometric analysis of 773 articles of interest showed that research in this field had continued to grow in recent years, with a high degree of interdisciplinary integration. Secondly, this field attached great importance to the quantitative analysis of Chinese medicine combined with nano/micro particle technology. Chinese medicine, nanoparticles and liposomes were the most accessed keywords. China was the main contributing country, and the top-10 contributing organizations were all located in China. Co-authorship was a common phenomenon in this field. Conclusion: The published literature on the application of nano/micro particle technology in Chinese medicine was summarized. The results suggested that bibliometric analysis could predict possible directions for future research in this field. [ABSTRACT FROM AUTHOR]

RNA modification includes four main types, N6-methyladenosine, N1- methyladenosine, alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing, involving 41 enzymes that serve as "writers", "readers" and "erasers". By collecting RNA modifying enzyme information in 1759 hepatobiliary malignancy (HBM) samples from 11 datasets, an RNA modification HBM Score (RH_score) was established based on unsupervised cluster analysis of RNA modification-associated differentially expressed genes (DEGs). We identified the imbalanced expression of 41 RNA modification enzymes in HBM, which was scientifically categorized into two groups: RH_Score high and RH_Score low. A high RH_Score was associated with a worse prognosis and more immature immune cells in the tumor microenvironment (TME), while a low RH_Score was associated with a better prognosis and more mature immune cells in the TME. Further analysis using single-cell databases showed that the high RH_Score was immune exhaustion in the TME. RH_Score was involved in transcriptional regulation and post-transcriptional events in HBM. Additionally, resistant and sensitive drugs were selected based on RNA modification, and anti-PD-L1 therapy responded better with low RH_Score. In conclusion, our study comprehensively analyzes RNA modification in HBM, which induces TME changes and transcriptional and posttranscriptional events, implying potential guiding significance in prognosis prediction and treatment options. [ABSTRACT FROM AUTHOR]

Introduction: Age-relatedmacular degeneration (AMD), an ever-increasing ocular disease, has become one of the leading causes of irreversible blindness. Recent advances in single-cell genomics are improving our understanding of the molecular mechanisms of AMD. However, the pathophysiology of this multifactorial disease is complicated and still an ongoing challenge. To better understand disease pathogenesis and identify effective targets, we conducted an in-depth analysis of the single-cell transcriptome of AMD. Methods: The cell expression specificity of the gene (CESG) was selected as an index to identify the novel cellmarkers. A computational framework was designed to explore the cell-specific TF regulatory loops, containing the interaction of gene pattern signatures, transcription factors regulons, and differentially expressed genes. Results: Three potential novel cell markers were DNASE1L3 for endothelial cells, ABCB5 for melanocytes, and SLC39A12 for RPE cells detected. We observed a notable change in the cell abundance and crosstalk of fibroblasts cells, melanocytes, schwann cells, and T/NK cells between AMD and controls, representing a complex cellular ecosystem in disease status. Finally, we identified six cell type related and three disease-associated ternary loops and elaborated on the robust association between key immune-pathway and AMD. Discussion: In conclusion, this study facilitates the optimization of screening for AMD-related receptor ligand pathways and proposes to further improve the interpretability of disease associations from single-cell data. It illuminated that immune-related regulation paths could be used as potential diagnostic markers for AMD, and in the future, also as therapeutic targets, providing insights into AMD diagnosis and potential interventions. [ABSTRACT FROM AUTHOR]

[Display omitted] • The crosstalk between different cells is fundamental to understand the processes of cognitive dysfunction. • The glial inclusions of tau play an important role in neurodegenerative diseases. • Synaptic plasticity depends on the intact crosstalk between neurons and glia in the brain. • Glia-related neuroinflammation plays a role in neurodegeneration. • The Glia-tau-neuron triangle could be the promoter of the synapse loss in tauopathies. Tauopathies are a group of neurodegenerative diseases among which are many of the most prevalent and with higher incidence worldwide, such as Alzheimer's disease (AD). According to the World Health Organization, this set of diseases will continue to increase their incidence, affecting millions of people by 2050. All of them are characterized by aberrant aggregation of tau protein in neurons and glia that are distributed in different brain regions according to their susceptibility. Numerous studies reveal that synaptic regulation not only has a neuronal component, but glia plays a fundamental role in it beyond its neuroinflammatory role. Despite this, it has not been emphasized how the glial inclusions of tau in this cell type directly affect this and many other essential functions, whose alterations have been related to the development of tauopathies. In this way, this review shows how tau inclusions in glia influence the synaptic dysfunctions that result in the cognitive symptoms characteristic of tauopathies. Thus, the mechanisms affected by inclusions in neurons, astrocytes, and oligodendrocytes are unraveled. [ABSTRACT FROM AUTHOR]

Liver cancer is the third greatest cause of cancer-related mortality, which of the major pathological type is hepatocellular carcinoma (HCC) accounting for more than 90%. HCC is characterized by high mortality and is predisposed to metastasis and relapse, leading to a low five-year survival rate and poor clinical prognosis. Numerous crosstalk among tumor parenchymal cells, anti-tumor cells, stroma cells, and immunosuppressive cells contributes to the immunosuppressive tumor microenvironment (TME), in which the function and frequency of anti-tumor cells are reduced with that of associated pro-tumor cells increasing, accordingly resulting in tumor malignant progression. Indeed, sorting out and understanding the signaling pathways and molecular mechanisms of cellular crosstalk in TME is crucial to discover more key targets and specific biomarkers, so that develop more efficient methods for early diagnosis and individualized treatment of liver cancer. This piece of writing offers insight into the recent advances in HCC-TME and reviews various mechanisms that promote HCC malignant progression from the perspective of mutual crosstalk among different types of cells in TME, aiming to assist in identifying the possible research directions and methods in the future for discovering new targets that could prevent HCC malignant progression. [ABSTRACT FROM AUTHOR]

The literature on the crosstalk between the brain and the gut has increased considerably in recent years. It is widely accepted now that the microbiome plays a significant role in several brain disorders, neurodevelopment, neurocognitive stages, and physiological functions. However, the mechanisms that influence such crosstalk are still not well elucidated. In this sense, one of the possible mechanisms by which the microbiome could influence brain function is through gut hormones released by enteroendocrine cells: ghrelin, cholecystokinin (CCK), peptide YY (PYY), vasoactive intestinal polypeptide (VIP), glucagon-like peptide (GLP1-2), corticotropin-releasing factor (CRF), glucose-dependent insulinotropic polypeptide (GIP), secretin, serotonin (5-HT), and oxytocin. Especially when one considers that the brain expresses receptors for these hormones in areas important to the neurobiology of brain disorders (e.g., depression), such as the hippocampus, amygdala, hypothalamus, and suprachiasmatic nucleus. To strengthen this hypothesis, gastrointestinal dysfunction (such as altered motility or pain) is relatively common in depressive patients, and changes in diet (low-carbohydrate diets, for example) positively affect mood. Additionally, alterations in the gut microbiome are relatively common in depressive patients and are related to the levels of Akkermansia, Lactobacillus, Bifidobacteria, Faecalibacterium, Roseburia and Clostridium. Finally, concerning the gut-released hormones, the literature reports that ghrelin can be a peripheral marker for the antidepressant treatment success rate and has elevated levels during depression. GLP-1 is tightly correlated with HPA axis activity being decreased by high cortisol levels. CCK seems to be altered in depression due to increased inflammation and activation of Toll-like receptor 4. Such finds allow the postulation that hormones, the microbiome and mood are intertwined and co-dependent. VIP is correlated with circadian rhythms. There is a bidirectional connection of the circadian rhythms between the host and the microbiota. Circadian rhythm disruption is associated with both poor outcomes in mental health and alterations in the microbiota composition. In sum, in the past year, more and more research has been published showing the tight connection between gut and brain health and trying to decipher the feedback in play. Here, we focus on depression. [ABSTRACT FROM AUTHOR]

Introduction: Sepsis is currently a common condition in emergency and intensive care units, and is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Cardiac dysfunction caused by septic myocardial injury (SMI) is associated with adverse prognosis and has significant economic and human costs. The pathophysiological mechanisms underlying SMI have long been a subject of interest. Recent studies have identified ferroptosis, a form of programmed cell death associated with iron accumulation and lipid peroxidation, as a pathological factor in the development of SMI. However, the current understanding of how ferroptosis functions and regulates in SMI remains limited, particularly in the absence of direct evidence from human heart. Methods: We performed a sequential comprehensive bioinformatics analysis of human sepsis cardiac transcriptome data obtained through the GEO database. The lipopolysaccharide-induced mouse SMI model was used to validate the ferroptosis features and transcriptional expression of key genes. Results: We identified widespread dysregulation of ferroptosis-related genes (FRGs) in SMI based on the human septic heart transcriptomes, deeply explored the underlying biological mechanisms and crosstalks, followed by the identification of key functional modules and hub genes through the construction of protein-protein interaction network. Eight key FRGs that regulate ferroptosis in SMI, including HIF1A, MAPK3, NOX4, PPARA, PTEN, RELA, STAT3 and TP53, were identified, as well as the ferroptosis features. All the key FRGs showed excellent diagnostic capability for SMI, part of them was associated with the prognosis of sepsis patients and the immune infiltration in the septic hearts, and potential ferroptosis-modulating drugs for SMI were predicted based on key FRGs. Conclusion: This study provides human septic heart transcriptome-based evidence and brings new insights into the role of ferroptosis in SMI, which is significant for expanding the understanding of the pathobiological mechanisms of SMI and exploring promising diagnostic and therapeutic targets for SMI. [ABSTRACT FROM AUTHOR]

Research over the past two decades has confirmed that noncoding RNAs (ncRNAs), which are abundant in cells from yeast to vertebrates, are no longer "junk" transcripts but functional regulators that can mediate various cellular and physiological processes. The dysregulation of ncRNAs is closely related to the imbalance of cellular homeostasis and the occurrence and development of various diseases. In mammals, ncRNAs, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), have been shown to serve as biomarkers and intervention targets in growth, development, immunity, and disease progression. The regulatory functions of lncRNAs on gene expression are usually mediated by crosstalk with miRNAs. The most predominant mode of lncRNA-miRNA crosstalk is the lncRNA-miRNA-mRNA axis, in which lncRNAs act as competing endogenous RNAs (ceRNAs). Compared to mammals, little attention has been given to the role and mechanism of the lncRNA-miRNAmRNA axis in teleost species. In this review, we provide current knowledge about the teleost lncRNA-miRNA-mRNA axis, focusing on its physiological and pathological regulation in growth and development, reproduction, skeletal muscle, immunity to bacterial and viral infections, and other stress-related immune responses. Herein, we also explored the potential application of the lncRNA-miRNA-mRNA axis in the aquaculture industry. These findings contribute to an enhanced understanding of ncRNA and ncRNA-ncRNA crosstalk in fish biology to improve aquaculture productivity, fish health and quality. [ABSTRACT FROM AUTHOR]

Constituted by various heterogeneous cells, the tumor microenvironment (TME) is capable of promoting tumor proliferation, invasion, and metastasis through extensive crosstalk. The pivotal factor influencing the survival time of patients and their response to immunotherapy lies in the intratumoral immune environment. We obtained 112 differential genes related to T cell-mediated tumor killing in LUAD by employing bioinformatics analysis on the basis of the TCGA and TISIDB databases. Then the 6-gene prognostic risk score model (CA9, OIP5, TIMP1, SEC11C, FURIN, and TLR10) was constructed by conducting univariate LASSO as well as multivariate Cox regression analyses. The median risk score was taken as the threshold to classify the samples into two groups. Survival analysis revealed that the low-risk group exhibited a more favorable prognosis. Subsequently, the Cox regression analysis combined with clinical information (age, gender, and pathological stage) and the risk score of LUAD patients demonstrated the potential of this model as an independent prognostic factor. The nomogram established based on clinical information and a risk score in combination with the calibration curve indicated that this model had good predictive ability. Notable enrichment of the differential genes from the high- and low-risk groups was discovered in immune-associated processes or pathways, as shown by the GO and KEGG enrichment analyses. The combined use of single-sample gene enrichment analysis (ssGSEA) and immunophenoscore (IPS) demonstrated heightened immune infiltration and IPS scores in the low-risk group, indicating that immunotherapy was likely to show good efficacy in patients from this group. To sum up, the prognostic model of LUAD constructed based on T-cell-mediated cell killing-related genes was not only capable of screening the prognosis of LUAD patients but was also used for screening those LUAD patients with high sensitivity to immunotherapy. Our study offered novel insights into the clinical treatment and prognostic prediction of LUAD patients. [ABSTRACT FROM AUTHOR]

Yes‐associated protein (YAP) and its homologue TAZ are transducers of several biochemical and biomechanical signals, integrating multiplexed inputs from the microenvironment into higher level cellular functions such as proliferation, differentiation and migration. Emerging evidence suggests that Ca2+ is a key second messenger that connects microenvironmental input signals and YAP/TAZ regulation. However, studies that directly modulate Ca2+ have reported contradictory YAP/TAZ responses: in some studies, a reduction in Ca2+ influx increases the activity of YAP/TAZ, while in others, an increase in Ca2+ influx activates YAP/TAZ. Importantly, Ca2+ and YAP/TAZ exhibit distinct spatiotemporal dynamics, making it difficult to unravel their connections from a purely experimental approach. In this study, we developed a network model of Ca2+‐mediated YAP/TAZ signalling to investigate how temporal dynamics and crosstalk of signalling pathways interacting with Ca2+ can alter the YAP/TAZ response, as observed in experiments. By including six signalling modules (e.g. GPCR, IP3‐Ca2+, kinases, RhoA, F‐actin and Hippo‐YAP/TAZ) that interact with Ca2+, we investigated both transient and steady‐state cell response to angiotensin II and thapsigargin stimuli. The model predicts that stimuli, Ca2+ transients and frequency‐dependent relationships between Ca2+ and YAP/TAZ are primarily mediated by cPKC, DAG, CaMKII and F‐actin. Simulation results illustrate the role of Ca2+ dynamics and CaMKII bistable response in switching the direction of changes in Ca2+‐induced YAP/TAZ activity. A frequency‐dependent YAP/TAZ response revealed the competition between upstream regulators of LATS1/2, leading to the YAP/TAZ non‐monotonic response to periodic GPCR stimulation. This study provides new insights into underlying mechanisms responsible for the controversial Ca2+–YAP/TAZ relationship observed in experiments. Key points: YAP/TAZ integrates biochemical and biomechanical inputs to regulate cellular functions, and Ca2+ acts as a key second messenger linking cellular inputs to YAP/TAZ.Studies have reported contradictory Ca2+–YAP/TAZ relationships for different cell types and stimuli.A network model of Ca2+‐mediated YAP/TAZ signalling was developed to investigate the underlying mechanisms of divergent Ca2+–YAP/TAZ relationships.The model predicts context‐dependent Ca2+ transient, CaMKII bistable response and frequency‐dependent activation of LATS1/2 upstream regulators as mechanisms governing the Ca2+–YAP/TAZ relationship.This study provides new insights into the underlying mechanisms of the controversial Ca2+–YAP/TAZ relationship to better understand the dynamics of cellular functions controlled by YAP/TAZ activity. [ABSTRACT FROM AUTHOR]

Background: Pulmonary vascular abnormalities pose a risk for severe life-threatening hemodynamic disturbances following surgical repair of congenital cardiac communications (CCCs). In the distal lung, small airways and vessels share a common microenvironment, where biological crosstalks take place. Because respiratory cells infected by viruses express a number of molecules with potential impact on airway and vascular remodeling, we decided to test the hypothesis that CCC patients carrying viral genomes in the airways might be at a higher risk for pulmonary (and systemic) hemodynamic disturbances postoperatively. Methods: Sixty patients were prospectively enrolled (age 11 [7–16] months, median with interquartile range). Preoperative pulmonary/systemic mean arterial pressure ratio (PAP/SAP) was 0.78 (0.63–0.88). The presence or absence of genetic material for respiratory viruses in nasopharyngeal and tracheal aspirates was investigated preoperatively in the absence of respiratory symptoms using real-time polymerase chain reaction (kit for detection of 19 pathogens). Post-cardiopulmonary bypass (CPB) inflammatory reaction was analyzed by measuring serum levels of 36 inflammatory proteins (immunoblotting) 4 h after its termination. Postoperative hemodynamics was assessed using continuous recording of PAP and SAP with calculation of PAP/SAP ratio. Results: Viral genomes were detected in nasopharynx and the trachea in 64% and 38% of patients, respectively. Rhinovirus was the most prevalent agent. The presence of viral genomes in the trachea was associated with an upward shift of postoperative PAP curve (p = 0.011) with a PAP/SAP of 0.44 (0.36–0.50) in patients who were positive versus 0.34 (0.30–0.45) in those who were negative (p = 0.008). The presence or absence of viral genomes in nasopharynx did not help predict postoperative hemodynamics. Postoperative PAP/SAP was positively correlated with post-CPB levels of interleukin-1 receptor antagonist (p = 0.026), macrophage migration inhibitory factor (p = 0.019) and monocyte chemoattractant protein-1 (p = 0.031), particularly in patients with virus-positive tracheal aspirates. Conclusions: Patients with CCCs carrying respiratory viral genomes in lower airways are at a higher risk for postoperative pulmonary hypertension, thus deserving special attention and care. Preoperative exposure to respiratory viruses and post-CPB inflammatory reaction seem to play a combined role in determining the postoperative behavior of the pulmonary circulation. [ABSTRACT FROM AUTHOR]

Pathway genes functionally participate in the same biological process. They typically act cooperatively, and none is considered dispensable. The dominant paradigm in drug discovery is the one-to-one strategy, which aims to find the most sensitive drug to act on an individual target. However, many complex diseases, such as cancer, are caused by dysfunction among multiple-gene pathways, not just one. Therefore, identifying pathway genes that are responsive to synthetic compounds in a global physiological environment may be more effective in drug discovery. The high redundancy of crosstalk between biological pathways, though, hints that the covariance matrix, which only connects genes with strong marginal correlations, may miss higher-level interactions, such as group interactions. We herein report the development of DPADM—a Drug-Pathway association Detection Model that infers pathways responsive to specific drugs. This model elucidates higher-level gene–gene interactions by evaluating the conditional dependencies between genes under different drug treatments. The advantage of the proposed method is demonstrated using simulation studies by comparing with another two methods. We applied this model to the Connectivity Map data set (CMap), and demonstrated that DPADM is able to identify many drug-pathway associations, such as mitoxantrone (MTX)- PI3K/AKT association, which targets the topological conditions of DNA transcription. Surprisingly, apart from identifying pathways corresponding to specific drugs, our methodology also revealed new drug-related pathways with functions similarly to those of seed genes. [ABSTRACT FROM AUTHOR]