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1.
Mol Cell ; 82(24): 4700-4711.e12, 2022 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-36384136

RESUMEN

Maintenance of energy level to drive movements and material exchange with the environment is a basic principle of life. AMP-activated protein kinase (AMPK) senses energy level and is a major regulator of cellular energy responses. The gamma subunit of AMPK senses elevated ratio of AMP to ATP and allosterically activates the alpha catalytic subunit to phosphorylate downstream effectors. Here, we report that knockout of AMPKγ, but not AMPKα, suppressed phosphorylation of eukaryotic translation elongation factor 2 (eEF2) induced by energy starvation. We identified PPP6C as an AMPKγ-regulated phosphatase of eEF2. AMP-bound AMPKγ sequesters PPP6C, thereby blocking dephosphorylation of eEF2 and thus inhibiting translation elongation to preserve energy and to promote cell survival. Further phosphoproteomic analysis identified additional targets of PPP6C regulated by energy stress in an AMPKγ-dependent manner. Thus, AMPKγ senses cellular energy availability to regulate not only AMPKα kinase, but also PPP6C phosphatase and possibly other effectors.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Biosíntesis de Proteínas , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Fosforilación , Factor 2 de Elongación Peptídica/metabolismo
2.
Nature ; 620(7975): 890-897, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37558881

RESUMEN

Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia1-6. Little is known about the metabolic regulation of the fate of lung epithelial cells. Here we report that deleting the mitochondrial electron transport chain complex I subunit Ndufs2 in lung epithelial cells during mouse gestation led to death during postnatal alveolar development. Affected mice displayed hypertrophic cells with AT2 and AT1 cell features, known as transitional cells. Mammalian mitochondrial complex I, comprising 45 subunits, regenerates NAD+ and pumps protons. Conditional expression of yeast NADH dehydrogenase (NDI1) protein that regenerates NAD+ without proton pumping7,8 was sufficient to correct abnormal alveolar development and avert lethality. Single-cell RNA sequencing revealed enrichment of integrated stress response (ISR) genes in transitional cells. Administering an ISR inhibitor9,10 or NAD+ precursor reduced ISR gene signatures in epithelial cells and partially rescued lethality in the absence of mitochondrial complex I function. Notably, lung epithelial-specific loss of mitochondrial electron transport chain complex II subunit Sdhd, which maintains NAD+ regeneration, did not trigger high ISR activation or lethality. These findings highlight an unanticipated requirement for mitochondrial complex I-dependent NAD+ regeneration in directing cell fate during postnatal alveolar development by preventing pathological ISR induction.


Asunto(s)
Células Epiteliales Alveolares , Diferenciación Celular , Linaje de la Célula , Pulmón , Mitocondrias , Estrés Fisiológico , Animales , Ratones , Células Epiteliales Alveolares/citología , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Pulmón/citología , Pulmón/metabolismo , Pulmón/patología , Mitocondrias/enzimología , Mitocondrias/metabolismo , NAD/metabolismo , NADH Deshidrogenasa/metabolismo , Protones , RNA-Seq , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Análisis de Expresión Génica de una Sola Célula
3.
Nat Methods ; 21(2): 267-278, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38191930

RESUMEN

It is poorly understood how different cells in a tissue organize themselves to support tissue functions. We describe the CytoCommunity algorithm for the identification of tissue cellular neighborhoods (TCNs) based on cell phenotypes and their spatial distributions. CytoCommunity learns a mapping directly from the cell phenotype space to the TCN space using a graph neural network model without intermediate clustering of cell embeddings. By leveraging graph pooling, CytoCommunity enables de novo identification of condition-specific and predictive TCNs under the supervision of sample labels. Using several types of spatial omics data, we demonstrate that CytoCommunity can identify TCNs of variable sizes with substantial improvement over existing methods. By analyzing risk-stratified colorectal and breast cancer data, CytoCommunity revealed new granulocyte-enriched and cancer-associated fibroblast-enriched TCNs specific to high-risk tumors and altered interactions between neoplastic and immune or stromal cells within and between TCNs. CytoCommunity can perform unsupervised and supervised analyses of spatial omics maps and enable the discovery of condition-specific cell-cell communication patterns across spatial scales.


Asunto(s)
Algoritmos , Redes Neurales de la Computación , Análisis por Conglomerados , Fenotipo
4.
Nature ; 599(7886): 650-656, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34732887

RESUMEN

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm3,4.


Asunto(s)
Complejo I de Transporte de Electrón/genética , Complejo I de Transporte de Electrón/metabolismo , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Animales , Axones/efectos de los fármacos , Axones/metabolismo , Axones/patología , Muerte Celular , Dendritas/metabolismo , Dendritas/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Femenino , Levodopa/farmacología , Levodopa/uso terapéutico , Masculino , Ratones , Destreza Motora/efectos de los fármacos , NADH Deshidrogenasa/deficiencia , NADH Deshidrogenasa/genética , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Fenotipo , Sustancia Negra/citología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo
6.
Proc Natl Acad Sci U S A ; 121(22): e2402764121, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38771879

RESUMEN

Staphylococcus aureus (S. aureus) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, S. aureus type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING's palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by S. aureus T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat S. aureus infections.


Asunto(s)
Proteínas Bacterianas , Macrófagos , Proteínas de la Membrana , Infecciones Estafilocócicas , Staphylococcus aureus , Sistemas de Secreción Tipo VII , Ubiquitinación , Staphylococcus aureus/inmunología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/inmunología , Humanos , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Animales , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/metabolismo , Sistemas de Secreción Tipo VII/metabolismo , Sistemas de Secreción Tipo VII/inmunología , Sistemas de Secreción Tipo VII/genética , Ratones , Evasión Inmune , Interacciones Huésped-Patógeno/inmunología
7.
Brief Bioinform ; 25(2)2024 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-38426323

RESUMEN

Most sequencing-based spatial transcriptomics (ST) technologies do not achieve single-cell resolution where each captured location (spot) may contain a mixture of cells from heterogeneous cell types, and several cell-type decomposition methods have been proposed to estimate cell type proportions of each spot by integrating with single-cell RNA sequencing (scRNA-seq) data. However, these existing methods did not fully consider the effect of distribution difference between scRNA-seq and ST data for decomposition, leading to biased cell-type-specific genes derived from scRNA-seq for ST data. To address this issue, we develop an instance-based transfer learning framework to adjust scRNA-seq data by ST data to correctly match cell-type-specific gene expression. We evaluate the effect of raw and adjusted scRNA-seq data on cell-type decomposition by eight leading decomposition methods using both simulated and real datasets. Experimental results show that data adjustment can effectively reduce distribution difference and improve decomposition, thus enabling for a more precise depiction on spatial organization of cell types. We highlight the importance of data adjustment in integrative analysis of scRNA-seq with ST data and provide guidance for improved cell-type decomposition.


Asunto(s)
Perfilación de la Expresión Génica , Análisis de Expresión Génica de una Sola Célula , Proyectos de Investigación , Análisis de Secuencia de ARN
8.
Brief Bioinform ; 25(4)2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-39003726

RESUMEN

Recent advances in chromatin conformation capture technologies, such as SPRITE and Pore-C, have enabled the detection of simultaneous contacts among multiple chromatin loci. This has made it possible to investigate the cooperative transcriptional regulation involving multiple genes and regulatory elements at the resolution of a single molecule. However, these technologies are unavoidably subject to the random polymer looping effect and technical biases, making it challenging to distinguish genuine regulatory relationships directly from random polymer interactions. Here, we present HyperloopFinder, a method for identifying regulatory multi-way chromatin contacts (hyperloops) by jointly modeling the random polymer looping effect and technical biases to estimate the statistical significance of multi-way contacts. The results show that our model can accurately estimate the expected interaction frequency of multi-way contacts based on the distance distribution of pairwise contacts, revealing that most multi-way contacts can be formed by randomly linking the pairwise contacts adjacent to each other. Moreover, we observed the spatial colocalization of the interaction sites of hyperloops from image-based data. Our results also revealed that hyperloops can function as scaffolds for the cooperation among multiple genes and regulatory elements. In summary, our work contributes novel insights into higher-order chromatin structures and functions and has the potential to enhance our understanding of transcriptional regulation and other cellular processes.


Asunto(s)
Cromatina , Modelos Estadísticos , Cromatina/química , Cromatina/metabolismo , Cromatina/genética , Humanos , Biología Computacional/métodos , Algoritmos , Regulación de la Expresión Génica
9.
Brief Bioinform ; 25(4)2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38980373

RESUMEN

Inferring gene regulatory networks (GRNs) allows us to obtain a deeper understanding of cellular function and disease pathogenesis. Recent advances in single-cell RNA sequencing (scRNA-seq) technology have improved the accuracy of GRN inference. However, many methods for inferring individual GRNs from scRNA-seq data are limited because they overlook intercellular heterogeneity and similarities between different cell subpopulations, which are often present in the data. Here, we propose a deep learning-based framework, DeepGRNCS, for jointly inferring GRNs across cell subpopulations. We follow the commonly accepted hypothesis that the expression of a target gene can be predicted based on the expression of transcription factors (TFs) due to underlying regulatory relationships. We initially processed scRNA-seq data by discretizing data scattering using the equal-width method. Then, we trained deep learning models to predict target gene expression from TFs. By individually removing each TF from the expression matrix, we used pre-trained deep model predictions to infer regulatory relationships between TFs and genes, thereby constructing the GRN. Our method outperforms existing GRN inference methods for various simulated and real scRNA-seq datasets. Finally, we applied DeepGRNCS to non-small cell lung cancer scRNA-seq data to identify key genes in each cell subpopulation and analyzed their biological relevance. In conclusion, DeepGRNCS effectively predicts cell subpopulation-specific GRNs. The source code is available at https://github.com/Nastume777/DeepGRNCS.


Asunto(s)
Aprendizaje Profundo , Redes Reguladoras de Genes , Análisis de la Célula Individual , Humanos , Análisis de la Célula Individual/métodos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Biología Computacional/métodos , Análisis de Secuencia de ARN/métodos , RNA-Seq/métodos
10.
Bioinformatics ; 40(4)2024 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-38507691

RESUMEN

MOTIVATION: The diverse structures and functions inherent in RNAs present a wealth of potential drug targets. Some small molecules are anticipated to serve as leading compounds, providing guidance for the development of novel RNA-targeted therapeutics. Consequently, the determination of RNA-small molecule binding affinity is a critical undertaking in the landscape of RNA-targeted drug discovery and development. Nevertheless, to date, only one computational method for RNA-small molecule binding affinity prediction has been proposed. The prediction of RNA-small molecule binding affinity remains a significant challenge. The development of a computational model is deemed essential to effectively extract relevant features and predict RNA-small molecule binding affinity accurately. RESULTS: In this study, we introduced RLaffinity, a novel deep learning model designed for the prediction of RNA-small molecule binding affinity based on 3D structures. RLaffinity integrated information from RNA pockets and small molecules, utilizing a 3D convolutional neural network (3D-CNN) coupled with a contrastive learning-based self-supervised pre-training model. To the best of our knowledge, RLaffinity was the first deep learning based method for the prediction of RNA-small molecule binding affinity. Our experimental results exhibited RLaffinity's superior performance compared to baseline methods, revealed by all metrics. The efficacy of RLaffinity underscores the capability of 3D-CNN to accurately extract both global pocket information and local neighbor nucleotide information within RNAs. Notably, the integration of a self-supervised pre-training model significantly enhanced predictive performance. Ultimately, RLaffinity was also proved as a potential tool for RNA-targeted drugs virtual screening. AVAILABILITY AND IMPLEMENTATION: https://github.com/SaisaiSun/RLaffinity.


Asunto(s)
Redes Neurales de la Computación , ARN , ARN/metabolismo , Descubrimiento de Drogas
11.
Bioinformatics ; 40(5)2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38715444

RESUMEN

MOTIVATION: Exploring potential associations between diseases can help in understanding pathological mechanisms of diseases and facilitating the discovery of candidate biomarkers and drug targets, thereby promoting disease diagnosis and treatment. Some computational methods have been proposed for measuring disease similarity. However, these methods describe diseases without considering their latent multi-molecule regulation and valuable supervision signal, resulting in limited biological interpretability and efficiency to capture association patterns. RESULTS: In this study, we propose a new computational method named DiSMVC. Different from existing predictors, DiSMVC designs a supervised graph collaborative framework to measure disease similarity. Multiple bio-entity associations related to genes and miRNAs are integrated via cross-view graph contrastive learning to extract informative disease representation, and then association pattern joint learning is implemented to compute disease similarity by incorporating phenotype-annotated disease associations. The experimental results show that DiSMVC can draw discriminative characteristics for disease pairs, and outperform other state-of-the-art methods. As a result, DiSMVC is a promising method for predicting disease associations with molecular interpretability. AVAILABILITY AND IMPLEMENTATION: Datasets and source codes are available at https://github.com/Biohang/DiSMVC.


Asunto(s)
Biología Computacional , Humanos , Biología Computacional/métodos , Enfermedad , Algoritmos , MicroARNs/genética , Programas Informáticos , Aprendizaje Automático
12.
Exp Cell Res ; 436(1): 113956, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38341081

RESUMEN

Patients with hepatocellular carcinoma (HCC) are vulnerable to drug resistance. Although drug resistance has been taken much attention to HCC therapy, little is known of regorafenib and regorafenib resistance (RR). This study aimed to determine the drug resistance pattern and the role of RhoA in RR. Two regorafenib-resistant cell lines were constructed based on Huh7 and Hep3B cell lines. In vitro and in vivo assays were conducted to study RhoA expression, the activity of Hippo signaling pathway and cancer stem cell (CSC) traits. The data showed that RhoA was highly expressed, Hippo signaling was hypoactivated and CSC traits were more prominent in RR cells. Inhibiting RhoA could reverse RR, and the alliance of RhoA inhibition and regorafenib synergistically attenuated CSC phenotype. Furthermore, inhibiting LARG/RhoA increased Kibra/NF2 complex formation, prevented YAP from shuttling into the nucleus and repressed CD44 mRNA expression. Clinically, the high expression of RhoA correlated with poor prognosis. LARG, RhoA, YAP1 and CD44 show positive correlation with each other. Thus, inhibition of RhoGEF/RhoA has the potential to reverse RR and repress CSC phenotype in HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Piridinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Vía de Señalización Hippo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Compuestos de Fenilurea/farmacología
13.
Proc Natl Acad Sci U S A ; 119(39): e2202178119, 2022 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-36122208

RESUMEN

Acute oxygen (O2) sensing is essential for adaptation of organisms to hypoxic environments or medical conditions with restricted exchange of gases in the lung. The main acute O2-sensing organ is the carotid body (CB), which contains neurosecretory chemoreceptor (glomus) cells innervated by sensory fibers whose activation by hypoxia elicits hyperventilation and increased cardiac output. Glomus cells have mitochondria with specialized metabolic and electron transport chain (ETC) properties. Reduced mitochondrial complex (MC) IV activity by hypoxia leads to production of signaling molecules (NADH and reactive O2 species) in MCI and MCIII that modulate membrane ion channel activity. We studied mice with conditional genetic ablation of MCIII that disrupts the ETC in the CB and other catecholaminergic tissues. Glomus cells survived MCIII dysfunction but showed selective abolition of responsiveness to hypoxia (increased [Ca2+] and transmitter release) with normal responses to other stimuli. Mitochondrial hypoxic NADH and reactive O2 species signals were also suppressed. MCIII-deficient mice exhibited strong inhibition of the hypoxic ventilatory response and altered acclimatization to sustained hypoxia. These data indicate that a functional ETC, with coupling between MCI and MCIV, is required for acute O2 sensing. O2 regulation of breathing results from the integrated action of mitochondrial ETC complexes in arterial chemoreceptors.


Asunto(s)
Complejo III de Transporte de Electrones , Oxígeno , Respiración , Animales , Hipoxia de la Célula/fisiología , Complejo III de Transporte de Electrones/genética , Complejo III de Transporte de Electrones/metabolismo , Canales Iónicos , Ratones , NAD/metabolismo , Oxígeno/metabolismo
14.
Mol Cancer ; 23(1): 96, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38730415

RESUMEN

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasia Residual , Humanos , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/diagnóstico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Pronóstico , Masculino , Femenino , Resultado del Tratamiento , Biomarcadores de Tumor , Persona de Mediana Edad , ADN Tumoral Circulante
15.
Small ; 20(1): e2304281, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37667446

RESUMEN

Van der Waals (vdW)-layered materials have drawn tremendous interests due to their unique properties. Atom intercalation in the vdW gap of layered materials can tune their electronic structure and generate unexpected properties. Here a chemical-scissor-mediated method that enables metal intercalation into transition metal dichalcogenides (TMDCs) in molten salts is reported. By using this approach, various guest metal atoms (Mn, Fe, Co, Ni, Cu, and Ag) are intercalated into various TMDC hosts (such as TiS2 , NbS2 , TaS2 , TiSe2 , NbSe2 , TaSe2 , and Ti0.5 V0.5 S2 ). The structure of the intercalated compound and intercalation mechanism are investigated. The results indicate that the vdW gap and valence state of TMDCs can be modified through metal intercalation, and the intercalation behavior is dictated by the electron work function. The adjustable charge transfer and intercalation endow a channel for rapid mass transfer to enhance the electrochemical performances. Such a chemical-scissor-mediated intercalation provides an approach to tune the physical and chemical properties of TMDCs, which may open an avenue in functional application ranging from energy conversion to electronics.

16.
Brief Bioinform ; 23(2)2022 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-35018405

RESUMEN

Since miRNAs can participate in the posttranscriptional regulation of gene expression, they may provide ideas for the development of new drugs or become new biomarkers for drug targets or disease diagnosis. In this work, we propose an miRNA-disease association prediction method based on meta-paths (MDPBMP). First, an miRNA-disease-gene heterogeneous information network was constructed, and seven symmetrical meta-paths were defined according to different semantics. After constructing the initial feature vector for the node, the vector information carried by all nodes on the meta-path instance is extracted and aggregated to update the feature vector of the starting node. Then, the vector information obtained by the nodes on different meta-paths is aggregated. Finally, miRNA and disease embedding feature vectors are used to calculate their associated scores. Compared with the other methods, MDPBMP obtained the highest AUC value of 0.9214. Among the top 50 predicted miRNAs for lung neoplasms, esophageal neoplasms, colon neoplasms and breast neoplasms, 49, 48, 49 and 50 have been verified. Furthermore, for breast neoplasms, we deleted all the known associations between breast neoplasms and miRNAs from the training set. These results also show that for new diseases without known related miRNA information, our model can predict their potential miRNAs. Code and data are available at https://github.com/LiangYu-Xidian/MDPBMP.


Asunto(s)
Neoplasias de la Mama , Neoplasias Pulmonares , MicroARNs , Algoritmos , Neoplasias de la Mama/genética , Biología Computacional/métodos , Femenino , Humanos , MicroARNs/genética , MicroARNs/metabolismo
17.
Brief Bioinform ; 23(2)2022 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-35021191

RESUMEN

Networks consisting of molecular interactions are intrinsically dynamical systems of an organism. These interactions curated in molecular interaction databases are still not complete and contain false positives introduced by high-throughput screening experiments. In this study, we propose a framework to integrate interactions of functional associated protein-coding genes from 31 data sources to reconstruct a network with high coverage and quality. For each interaction, 369 features were constructed including properties of both the interaction and the involved genes. The training and validation sets were built on the pathway interactions as positives and the potential negative instances resulting from our proposed semi-supervised strategy. Random forest classification method was then applied to train and predict multiple times to give a score for each interaction. After setting a threshold estimated by a Binomial distribution, a Human protein-coding Gene Functional Association Network (HuGFAN) was reconstructed with 20 383 genes and 1185 429 high confidence interactions. Then, HuGFAN was compared with other networks from data sources with respect to network properties, suggesting that HuGFAN is more function and pathway related. Finally, HuGFAN was applied to identify cancer driver through two famous network-based methods (DriverNet and HotNet2) to show its outstanding performance compared with other networks. HuGFAN and other supplementary files are freely available at https://github.com/xthuang226/HuGFAN.


Asunto(s)
Redes Reguladoras de Genes , Aprendizaje Automático , Bases de Datos Factuales , Humanos
18.
Brief Bioinform ; 23(3)2022 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-35246678

RESUMEN

With an in-depth understanding of noncoding ribonucleic acid (RNA), many studies have shown that microRNA (miRNA) plays an important role in human diseases. Because traditional biological experiments are time-consuming and laborious, new calculation methods have recently been developed to predict associations between miRNA and diseases. In this review, we collected various miRNA-disease association prediction models proposed in recent years and used two common data sets to evaluate the performance of the prediction models. First, we systematically summarized the commonly used databases and similarity data for predicting miRNA-disease associations, and then divided the various calculation models into four categories for summary and detailed introduction. In this study, two independent datasets (D5430 and D6088) were compiled to systematically evaluate 11 publicly available prediction tools for miRNA-disease associations. The experimental results indicate that the methods based on information dissemination and the method based on scoring function require shorter running time. The method based on matrix transformation often requires a longer running time, but the overall prediction result is better than the previous two methods. We hope that the summary of work related to miRNA and disease will provide comprehensive knowledge for predicting the relationship between miRNA and disease and contribute to advanced computation tools in the future.


Asunto(s)
MicroARNs , Algoritmos , Biología Computacional/métodos , Predisposición Genética a la Enfermedad , Humanos , MicroARNs/genética
19.
Bioinformatics ; 39(2)2023 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-36707990

RESUMEN

MOTIVATION: The emergence of drug-resistant bacteria makes the discovery of new antibiotics an urgent issue, but finding new molecules with the desired antibacterial activity is an extremely difficult task. To address this challenge, we established a framework, MDAGS (Molecular Design via Attribute-Guided Search), to optimize and generate potent antibiotic molecules. RESULTS: By designing the antibacterial activity latent space and guiding the optimization of functional compounds based on this space, the model MDAGS can generate novel compounds with desirable antibacterial activity without the need for extensive expensive and time-consuming evaluations. Compared with existing antibiotics, candidate antibacterial compounds generated by MDAGS always possessed significantly better antibacterial activity and ensured high similarity. Furthermore, although without explicit constraints on similarity to known antibiotics, these candidate antibacterial compounds all exhibited the highest structural similarity to antibiotics of expected function in the DrugBank database query. Overall, our approach provides a viable solution to the problem of bacterial drug resistance. AVAILABILITY AND IMPLEMENTATION: Code of the model and datasets can be downloaded from GitHub (https://github.com/LiangYu-Xidian/MDAGS). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Antibacterianos , Bacterias , Antibacterianos/farmacología , Antibacterianos/química , Bases de Datos Factuales
20.
J Neurovirol ; 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38926255

RESUMEN

Caffeine is one of the most popular consumed psychostimulants that mitigates several neurodegenerative diseases. Nevertheless, the roles and molecular mechanisms of caffeine in HIV-associated neurocognitive disorders (HAND) remain largely unclear. Transactivator of transcription (Tat) is a major contributor to the neuropathogenesis of HAND in the central nervous system. In the present study, we determined that caffeine (100 µM) treatment significantly ameliorated Tat-induced decreased astrocytic viability, oxidative stress, inflammatory response and excessive glutamate and ATP release, thereby protecting neurons from apoptosis. Subsequently, SIRT3 was demonstrated to display neuroprotective effects against Tat during caffeine treatment. In addition, Tat downregulated SIRT3 expression via activation of EGR1 signaling, which was reversed by caffeine treatment in astrocytes. Overexpression of EGR1 entirely abolished the neuroprotective effects of caffeine against Tat. Furthermore, counteracting Tat or caffeine-induced differential expression of SIRT3 abrogated the neuroprotection of caffeine against Tat-triggered astrocytic dysfunction and neuronal apoptosis. Taken together, our study establishes that caffeine ameliorates astrocytes-mediated Tat neurotoxicity by targeting EGR1/SIRT3 signaling pathway. Our findings highlight the beneficial effects of caffeine on Tat-induced astrocytic dysfunction and neuronal death and propose that caffeine might be a novel therapeutic drug for relief of HAND.

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