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Bioinformatics (Oxford, England) Jun 2024In drug discovery, it is crucial to assess the drug-target binding affinity (DTA). Although molecular docking is widely used, computational efficiency limits its...
MOTIVATION
In drug discovery, it is crucial to assess the drug-target binding affinity (DTA). Although molecular docking is widely used, computational efficiency limits its application in large-scale virtual screening. Deep learning-based methods learn virtual scoring functions from labeled datasets and can quickly predict affinity. However, there are three limitations. First, existing methods only consider the atom-bond graph or one-dimensional sequence representations of compounds, ignoring the information about functional groups (pharmacophores) with specific biological activities. Second, relying on limited labeled datasets fails to learn comprehensive embedding representations of compounds and proteins, resulting in poor generalization performance in complex scenarios. Third, existing feature fusion methods cannot adequately capture contextual interaction information.
RESULTS
Therefore, we propose a novel DTA prediction method named HeteroDTA. Specifically, a multi-view compound feature extraction module is constructed to model the atom-bond graph and pharmacophore graph. The residue concat graph and protein sequence are also utilized to model protein structure and function. Moreover, to enhance the generalization capability and reduce the dependence on task-specific labeled data, pre-trained models are utilized to initialize the atomic features of the compounds and the embedding representations of the protein sequence. A context-aware nonlinear feature fusion method is also proposed to learn interaction patterns between compounds and proteins. Experimental results on public benchmark datasets show that HeteroDTA significantly outperforms existing methods. In addition, HeteroDTA shows excellent generalization performance in cold-start experiments and superiority in the representation learning ability of drug-target pairs. Finally, the effectiveness of HeteroDTA is demonstrated in a real-world drug discovery study.
AVAILABILITY AND IMPLEMENTATION
The source code and data are available at https://github.com/daydayupzzl/HeteroDTA.
Topics: Drug Discovery; Molecular Docking Simulation; Proteins; Deep Learning; Pharmacophore
PubMed: 38940179
DOI: 10.1093/bioinformatics/btae240 -
Bioinformatics (Oxford, England) Jun 2024Profiling of gene expression and chromatin accessibility by single-cell multi-omics approaches can help to systematically decipher how transcription factors (TFs)...
MOTIVATION
Profiling of gene expression and chromatin accessibility by single-cell multi-omics approaches can help to systematically decipher how transcription factors (TFs) regulate target gene expression via cis-region interactions. However, integrating information from different modalities to discover regulatory associations is challenging, in part because motif scanning approaches miss many likely TF binding sites.
RESULTS
We develop REUNION, a framework for predicting genome-wide TF binding and cis-region-TF-gene "triplet" regulatory associations using single-cell multi-omics data. The first component of REUNION, Unify, utilizes information theory-inspired complementary score functions that incorporate TF expression, chromatin accessibility, and target gene expression to identify regulatory associations. The second component, Rediscover, takes Unify estimates as input for pseudo semi-supervised learning to predict TF binding in accessible genomic regions that may or may not include detected TF motifs. Rediscover leverages latent chromatin accessibility and sequence feature spaces of the genomic regions, without requiring chromatin immunoprecipitation data for model training. Applied to peripheral blood mononuclear cell data, REUNION outperforms alternative methods in TF binding prediction on average performance. In particular, it recovers missing region-TF associations from regions lacking detected motifs, which circumvents the reliance on motif scanning and facilitates discovery of novel associations involving potential co-binding transcriptional regulators. Newly identified region-TF associations, even in regions lacking a detected motif, improve the prediction of target gene expression in regulatory triplets, and are thus likely to genuinely participate in the regulation.
AVAILABILITY AND IMPLEMENTATION
All source code is available at https://github.com/yangymargaret/REUNION.
Topics: Transcription Factors; Humans; Single-Cell Analysis; Binding Sites; Chromatin; Genomics; Software; Computational Biology; Protein Binding; Algorithms; Leukocytes, Mononuclear; Multiomics
PubMed: 38940155
DOI: 10.1093/bioinformatics/btae234 -
Bioinformatics (Oxford, England) Jun 2024Mutations are the crucial driving force for biological evolution as they can disrupt protein stability and protein-protein interactions which have notable impacts on...
MOTIVATION
Mutations are the crucial driving force for biological evolution as they can disrupt protein stability and protein-protein interactions which have notable impacts on protein structure, function, and expression. However, existing computational methods for protein mutation effects prediction are generally limited to single point mutations with global dependencies, and do not systematically take into account the local and global synergistic epistasis inherent in multiple point mutations.
RESULTS
To this end, we propose a novel spatial and sequential message passing neural network, named DDAffinity, to predict the changes in binding affinity caused by multiple point mutations based on protein 3D structures. Specifically, instead of being on the whole protein, we perform message passing on the k-nearest neighbor residue graphs to extract pocket features of the protein 3D structures. Furthermore, to learn global topological features, a two-step additive Gaussian noising strategy during training is applied to blur out local details of protein geometry. We evaluate DDAffinity on benchmark datasets and external validation datasets. Overall, the predictive performance of DDAffinity is significantly improved compared with state-of-the-art baselines on multiple point mutations, including end-to-end and pre-training based methods. The ablation studies indicate the reasonable design of all components of DDAffinity. In addition, applications in nonredundant blind testing, predicting mutation effects of SARS-CoV-2 RBD variants, and optimizing human antibody against SARS-CoV-2 illustrate the effectiveness of DDAffinity.
AVAILABILITY AND IMPLEMENTATION
DDAffinity is available at https://github.com/ak422/DDAffinity.
Topics: Point Mutation; SARS-CoV-2; Computational Biology; Protein Conformation; Humans; Neural Networks, Computer; Protein Binding; COVID-19; Proteins; Algorithms
PubMed: 38940145
DOI: 10.1093/bioinformatics/btae232 -
Frontiers in Bioscience (Landmark... Jun 2024Transcription factors (TFs) are essential proteins regulating gene expression by binding to specific nucleotide sequences upstream of genes. Among TF families, the... (Review)
Review
Transcription factors (TFs) are essential proteins regulating gene expression by binding to specific nucleotide sequences upstream of genes. Among TF families, the forkhead box (FOX) proteins, characterized by a conserved DNA-binding domain, play vital roles in various cellular processes, including cancer. The FOXA subfamily, encompassing FOXA1, FOXA2, and FOXA3, stands out for its pivotal role in mammalian development. FOXA1, initially identified in the liver, exhibits diverse expression across multiple organ tissues and plays a critical role in cell proliferation, differentiation, and tumor development. Its structural composition includes transactivation domains and a DNA-binding domain, facilitating its function as a pioneer factor, which is crucial for chromatin interaction and the recruitment of other transcriptional regulators. The involvement of FOXA1 in sex hormone-related tumors underscores its significance in cancer biology. This review provides an overview of multifaceted roles of FOXA1 in normal development and its implications in the pathogenesis of hormone-related cancers, particularly breast cancer and prostate cancer.
Topics: Humans; Hepatocyte Nuclear Factor 3-alpha; Male; Female; Breast Neoplasms; Prostatic Neoplasms; Gonadal Steroid Hormones; Neoplasms; Animals; Gene Expression Regulation, Neoplastic
PubMed: 38940052
DOI: 10.31083/j.fbl2906225 -
Frontiers in Bioscience (Landmark... Jun 2024Hormone receptors exert their function through binding with their ligands, which results in cellular signaling activation mediated by genomic or non-genomic mechanisms....
BACKGROUND
Hormone receptors exert their function through binding with their ligands, which results in cellular signaling activation mediated by genomic or non-genomic mechanisms. The intrinsic molecular communication of tick and its host comprises an endocrine regulation involving hormones. In the present study, we performed a molecular and analysis of a Membrane Associated Progesterone Receptor in (RmMAPRC).
METHODS
The RmMAPRC protein sequence was analyzed with bioinformatics tools, and its structure was characterized by three-dimensional (3D) modeling and molecular docking. A semi-quantitative reverse transcription and polymerase chain reaction (sqRT-PCR) assessed the gene presence and relative expression in tick organs and embryonic cells.
RESULTS
relative expression in salivary glands, ovaries, and embryonic cells showed overexpression of 3%, 13%, and 24%, respectively. Bioinformatic analysis revealed that RmMAPRC corresponded to a Progesterone Receptor Membrane Component 1 (RmPGRMC1) of ~23.7 kDa, with an N-terminal transmembrane domain and a C-terminal Cytochrome b5-like heme/steroid binding domain. The docking results suggest that RmPGRMC1 could bind to progesterone (P4), some progestins, and P4 antagonists. The phylogenetic reconstruction showed that spp. MAPRC receptors were clustered in a clade that includes , , and (RmMAPRC), and mammals and helminths MAPRC receptors clustered in two separated clades away from ticks.
CONCLUSIONS
The presence of RmPGRMC1 highlights the importance of transregulation as a conserved adaptive mechanism that has succeeded for arthropod parasites, making it a target for tick control.
Topics: Animals; Rhipicephalus; Receptors, Progesterone; Progesterone; Cattle; Molecular Docking Simulation; Host-Parasite Interactions; Female; Amino Acid Sequence; Protein Binding; Phylogeny
PubMed: 38940045
DOI: 10.31083/j.fbl2906238 -
Frontiers in Bioscience (Landmark... Jun 2024This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated...
BACKGROUND
This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated by TIG1 in melanoma cells and its impact on cell growth.
METHODS
The effects of TIG1 expression on cell viability and death were assessed using water-soluble tetrazolium 1 (WST-1) mitochondrial staining and lactate dehydrogenase release assays. RNA sequencing and Western blot analysis were employed to investigate the genes regulated by TIG1 in melanoma cells. Additionally, the correlation between expression and its downstream genes was analyzed in a melanoma tissue array.
RESULTS
TIG1 expression in melanoma cells was associated with decreased cell viability and increased cell death. RNA-sequencing (RNA-seq), quantitative reverse transcription PCR (reverse RT-QPCR), and immunoblots revealed that TIG1 expression induced the expression of Endoplasmic Reticulum (ER) stress response-related genes such as Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (HERPUD1), Binding immunoglobulin protein (BIP), and DNA damage-inducible transcript 3 (DDIT3). Furthermore, analysis of the melanoma tissue array revealed a positive correlation between expression and the expression of , , and . Additionally, attenuation of the ER stress response in melanoma cells weakened the impact of TIG1 on cell growth.
CONCLUSIONS
TIG1 expression effectively hinders the growth of melanoma cells. TIG1 induces the upregulation of ER stress response-related genes, leading to an increase in caspase-3 activity and subsequent cell death. These findings suggest that the ability of retinoic acid to prevent melanoma formation may be associated with the anticancer effect of TIG1.
Topics: Humans; Endoplasmic Reticulum Stress; Melanoma; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Cell Death; Apoptosis; Cell Proliferation; Membrane Proteins
PubMed: 38940043
DOI: 10.31083/j.fbl2906233 -
Frontiers in Bioscience (Landmark... Jun 2024Gastric cancer (GC) is a leading cause of cancer-associated death worldwide. Its molecular mechanisms, especially concerning autophagy and various signaling pathways,...
BACKGROUND
Gastric cancer (GC) is a leading cause of cancer-associated death worldwide. Its molecular mechanisms, especially concerning autophagy and various signaling pathways, are not fully understood. Fatty Acid Binding Protein 6 () and RE1 Silencing Transcription Factor () emerge as potential key players in this context. This study sought to analyze the functional relationship of and concerning autophagy and their implications on the Akt/mTOR signaling pathway within GC cells.
METHODS
A comprehensive bioinformatics approach was used to identify key prognostic markers in GC. The effects of and on autophagy along with Akt/mTOR signaling pathways were analyzed by techniques including Western blotting (WB), flow cytometry, Transwell assay, dual luciferase reporter assay, and others.
RESULTS
was identified as overexpressed in GC, linked with poor prognosis. silencing reduces GC cell proliferation, induces S- and G2-phase arrest, and downregulates cyclins CDK2 and CDK4. It also inhibited GC cell invasion/migration and autophagy, effects that were counteracted by MG132. When combined with PI3K inhibitor LY294002c, knockdown showed synergistic anti-proliferative effects, modulating the Akt/mTOR pathway. Besides, the transcription factor has been shown to directly regulate expression, affecting autophagy and the Akt/mTOR signaling pathway in a -dependent manner.
CONCLUSIONS
positively regulates autophagy and negatively affects the Akt/mTOR signaling pathway in GC cells in a FABP6-dependent manner, providing valuable insights into regulatory networks involving and .
Topics: Humans; Stomach Neoplasms; TOR Serine-Threonine Kinases; Autophagy; Proto-Oncogene Proteins c-akt; Signal Transduction; Cell Line, Tumor; Fatty Acid-Binding Proteins; Cell Proliferation; Gene Expression Regulation, Neoplastic
PubMed: 38940038
DOI: 10.31083/j.fbl2906212 -
Frontiers in Bioscience (Landmark... Jun 2024Rheumatic heart disease (RHD) is caused by inflammatory cells mistakenly attacking the heart valve due to Group A Streptococcus (GAS) infection, but it is still unclear...
BACKGROUND
Rheumatic heart disease (RHD) is caused by inflammatory cells mistakenly attacking the heart valve due to Group A Streptococcus (GAS) infection, but it is still unclear which cells or genes are involved in the process of inflammatory cells infiltrating the valve. Inflammatory infiltration into the target tissue requires an increase in the expression of phosphorylated vascular endothelial-cadherin (p-VE-cad), p-VE-cad can increase the endothelial permeability and promote the migration of inflammatory cells across the endothelium. P-VE-cad is potentially regulated by RAS-related C3 botulinum substrate 1 (RAC1), together with phosphorylated proline-rich tyrosine kinase 2 (p-PYK2). While RAC1/p-PYK2/p-VE-cad is triggered by the activation of vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 is related to M1 macrophages adhering to the endothelium via very late antigen 4 (VLA4). Inflammatory infiltration into the valve is extremely important in the early pathogenesis of RHD. However, there is no relevant research on whether M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad is involved in RHD; therefore, what we explored in this study was whether M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad is involved.
METHODS
We established a rat model of RHD and a cell model of M1 macrophage and endothelial cell cocultivation. Subsequently, we measured the degree of inflammatory cell infiltration, the levels of IL-6/IL-17, the degree of fibrosis (COL3/1), and the expression levels of fibrosis markers (FSP1, COL1A1 and COL3A1) in the heart valves of RHD rats. Additionally, we detected the expression of M1/M2 macrophage biomarkers in rat model and cell model, as well as the expression of M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad. We also tested the changes in endothelial permeability after coculturing M1 macrophages and endothelial cells.
RESULTS
Compared to those in the control group, the levels of inflammatory cell infiltration and fibrotic factors in the heart valves of RHD rats were significantly higher; the expression of M1 macrophage biomarkers (iNOS, CD86 and TNF-α) in RHD rats was significantly higher; and significantly higher than the expression of M2 macrophage biomarkers (Arg1 and TGF-β). And the expression levels of VLA4/VCAM-1 and RAC1/p-PYK2/p-VE-cad in the hearts of RHD rats were significantly higher. At the cellular level, after coculturing M1 macrophages with endothelial cells, the expression levels of VLA4/VCAM-1 and RAC1/p-PYK2/p-VE-cad were significantly higher, and the permeability of the endothelium was significantly greater due to cocultivation with M1 macrophages.
CONCLUSIONS
All the results suggested that M1 macrophages and the VLA4/VCAM-1 pathway are potentially involved in the process of inflammatory infiltration in RHD.
Topics: Animals; Rheumatic Heart Disease; Vascular Cell Adhesion Molecule-1; Macrophages; Rats; Integrin alpha4beta1; Male; Heart Valves; Signal Transduction; Rats, Sprague-Dawley; rac1 GTP-Binding Protein; Disease Models, Animal; Humans
PubMed: 38940032
DOI: 10.31083/j.fbl2906219 -
Frontiers in Bioscience (Landmark... Jun 2024The senescence marker protein 30 (SMP30) is a calcium-binding protein whose expression decreases with age, and is closely associated with hepatocellular carcinoma (HCC)...
BACKGROUND
The senescence marker protein 30 (SMP30) is a calcium-binding protein whose expression decreases with age, and is closely associated with hepatocellular carcinoma (HCC) development. The primary goal of this study was to examine the mechanistic effect of SMP30 on HCC migration and invasion.
METHODS
Bioinformatic and immunohistochemical approaches were used to examine the expression of SMP30 in HCC tissues and its relationship to patient survival. We investigated the effects of SMP30 expression on HCC cell proliferation, migration, invasion, and cell cycle dynamics. cDNA microarray technology was used to determine the gene expression profile of SK-Hep-1 cells following recombinant SMP30 overexpression to identify genes downstream of SMP30 that regulate HCC cell migration and invasion. We identified SMP30 interacting proteins by affinity purification-mass spectrometry (AP-MS) and co-immunoprecipitation/western blotting (COIP-WB).
RESULTS
SMP30 expression was lower in HCC tissues compared with normal liver tissues, and its expression positively correlated with overall survival in HCC patients. Additionally, SMP30 overexpression effectively blocked the migratory and invasive properties of SK-Hep-1 cells, but did not affect either proliferation rates or cell cycle. cDNA microarray results confirmed that many of the differentially expressed genes identified are involved in the process of epithelial-mesenchymal transition (EMT). AP-MS and COIP-WB experiments confirmed that Rho-associated protein kinase 1 (ROCK1) interacts with SMP30 in SK-Hep-1 cells, and ROCK1 is known to intimately regulate the EMT process.
CONCLUSION
SMP30 inhibits HCC metastasis by influencing the expression of EMT-related proteins after interacting with ROCK1.
Topics: Humans; rho-Associated Kinases; Epithelial-Mesenchymal Transition; Carcinoma, Hepatocellular; Liver Neoplasms; Calcium-Binding Proteins; Neoplasm Invasiveness; Cell Line, Tumor; Cell Movement; Cell Proliferation; Intracellular Signaling Peptides and Proteins; Male; Female; Gene Expression Regulation, Neoplastic
PubMed: 38940025
DOI: 10.31083/j.fbl2906214 -
Frontiers in Bioscience (Elite Edition) May 2024Flaxseed mucilage (FSM) is one of the healthy components of flaxseed. FSM is an example of a material that can be used in the food, cosmetic, and pharmaceutical...
BACKGROUND
Flaxseed mucilage (FSM) is one of the healthy components of flaxseed. FSM is an example of a material that can be used in the food, cosmetic, and pharmaceutical industries due to its rheological properties. FSM consists mainly of two polysaccharides, arabinoxylan, and rhamnogalacturonan I, and it also contains protein components and minerals. The prospect of using FSM in food is due to its gelling, water binding, emulsifying, and foaming properties. In addition, valuable natural sources of phenolic compounds such as lignans, phenolic acids, flavonoids, phenylpropanoids, and tannins are partially extracted from flaxseed in FSM. These antioxidant components have pharmacological properties, including anti-diabetic, anti-hypertensive, immunomodulatory, anti-inflammatory and neuroprotective properties. A combination of FSM and lactobacilli in dairy foods can improve their functional properties. This study aimed to develop dairy products by adding of FSM and using two lactic acid bacteria (LAB). FSM (0.2%) was used as an ingredient to improve both the texture and antioxidant properties of the product.
METHODS
Skim milk was fermented with 0.2% flaxseed mucilage using and the probiotic AG9. The finished fermented milk products were stored at 4 °C for 14 days. Quantitative chemical, textural, and antioxidant analyses were carried out.
RESULTS
Adding 0.2% FSM to the dairy product stimulated the synthesis of lactic acid. FSM increased the viscosity and water-holding capacity of or AG9 fermented milk products. Combining these starter strains with FSM promoted the formation of a hard, elastic, resilient casein matrix in the product. When only AG9 was used for the fermentation, the dairy product had a high syneresis and a low viscosity and firmness; such a product is inferior in textural characteristics to the variant with commercial . The addition of FSM improved the textural properties of this variant. The use of AG9 and FSM makes it possible to obtain a fermented milk product with the highest content of polyphenolic compounds, which have the highest antioxidant properties and stimulate lipase and α-glucosidase inhibitor synthesis. Combining of and AG9 in the starter (20% of the total mass of the starter) and adding of 0.2% FSM is the optimal combination for obtaining a dairy product with high textural and antioxidant properties.
CONCLUSIONS
The physicochemical properties (viscosity, syneresis, water holding capacity, texture) and antioxidant properties of fermented milk were improved. In the future, as part of the work to investigate the functional properties of dairy products with FSM, studies will be conducted using in models.
Topics: Flax; Lactobacillus delbrueckii; Plant Mucilage; Lactobacillus plantarum; Antioxidants; Cultured Milk Products; Animals; Milk; Fermentation
PubMed: 38939910
DOI: 10.31083/j.fbe1602011