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DNA N6 methyladenine (6mA) plays an important role in many biological processes, and accurately identifying its sites helps one to understand its biological effects more comprehensively. Previous traditional experimental methods are very labor-intensive and traditional machine learning methods also seem to be somewhat insufficient as the database of 6mA methylation groups becomes progressively larger, so we propose a deep learning-based method called multi-scale convolutional model based on global response normalization (CG6mA) to solve the prediction problem of 6mA site. This method is tested with other methods on three different kinds of benchmark datasets, and the results show that our model can get more excellent prediction results.
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Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool in genomics research, enabling the analysis of gene expression at the individual cell level. However, scRNA-seq data often suffer from a high rate of dropouts, where certain genes fail to be detected in specific cells due to technical limitations. This missing data can introduce biases and hinder downstream analysis. To overcome this challenge, the development of effective imputation methods has become crucial in the field of scRNA-seq data analysis. Here, we propose an imputation method based on robust and non-negative matrix factorization (scRNMF). Instead of other matrix factorization algorithms, scRNMF integrates two loss functions: L2 loss and C-loss. The L2 loss function is highly sensitive to outliers, which can introduce substantial errors. We utilize the C-loss function when dealing with zero values in the raw data. The primary advantage of the C-loss function is that it imposes a smaller punishment for larger errors, which results in more robust factorization when handling outliers. Various datasets of different sizes and zero rates are used to evaluate the performance of scRNMF against other state-of-the-art methods. Our method demonstrates its power and stability as a tool for imputation of scRNA-seq data.
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Cirrhosis impairs macrophage function and disrupts bile acid homeostasis. Although bile acids affect macrophage function in patients with sepsis, whether and how the bile acid profile is changed by infection in patients with cirrhosis to modulate macrophage function remains unclear. The present study aimed to investigate the changes in the bile acid profile of patients with cirrhosis and infection and their effects on macrophage function. Serum was collected from 20 healthy subjects, 18 patients with cirrhosis and 39 patients with cirrhosis and infection. Bile acid profiles were detected using highperformance liquid chromatographytriple timeofflight mass spectrometer. The association between bile acid changes and infection was analysed using receiver operating characteristic (ROC) curves. Infectionaltered bile acids were used in combination with lipopolysaccharides (LPS) to stimulate RAW264.7/THP1 cells in vitro. The migratory capacity was evaluated using wound healing and Transwell migration assays. The expression of Arg1, iNOS, IκBα, phosphorylated (p)IκBα and p65 was examined with western blotting and immunofluorescence, Tnfα, Il1b and Il6 mRNA was examined with RTqPCR, and CD86, CD163 and phagocytosis was measured with flow cytometry. The ROC curves showed that decreased hyodeoxycholic acid (HDCA) and deoxycholic acid (DCA) levels were associated with infection. HDCA or DCA combined with LPS enhanced the phagocytic and migratory ability of macrophages, accompanied by upregulation of iNOS and CD86 protein expression as well as Tnfα, Il1b, and Il6 mRNA expression. However, neither HDCA nor DCA alone showed an effect on these phenotypes. In addition, DCA and HDCA acted synergistically with LPS to increase the expression of pIκBα and the intranuclear migration of p65. Infection changed the bile acid profile in patients with cirrhosis, among which the reduction of DCA and HDCA associated most strongly with infection. HDCA and DCA enhanced the sensitivity of macrophage function loss to LPS stimulation. These findings suggested a potential role for monitoring the bile acid profile that could help manage patients with cirrhosis and infection.
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Ácidos y Sales Biliares , Cirrosis Hepática , Activación de Macrófagos , Macrófagos , Humanos , Cirrosis Hepática/metabolismo , Activación de Macrófagos/efectos de los fármacos , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/sangre , Masculino , Femenino , Persona de Mediana Edad , Ratones , Células RAW 264.7 , Animales , Macrófagos/metabolismo , Macrófagos/inmunología , Lipopolisacáridos , Células THP-1 , Adulto , Anciano , Fagocitosis/efectos de los fármacos , Citocinas/metabolismo , Movimiento Celular/efectos de los fármacosRESUMEN
De novo drug design is crucial in advancing drug discovery, which aims to generate new drugs with specific pharmacological properties. Recently, deep generative models have achieved inspiring progress in generating drug-like compounds. However, the models prioritize a single target drug generation for pharmacological intervention, neglecting the complicated inherent mechanisms of diseases, and influenced by multiple factors. Consequently, developing novel multi-target drugs that simultaneously target specific targets can enhance anti-tumor efficacy and address issues related to resistance mechanisms. To address this issue and inspired by Generative Pre-trained Transformers (GPT) models, we propose an upgraded GPT model with generative adversarial imitation learning for multi-target molecular generation called MTMol-GPT. The multi-target molecular generator employs a dual discriminator model using the Inverse Reinforcement Learning (IRL) method for a concurrently multi-target molecular generation. Extensive results show that MTMol-GPT generates various valid, novel, and effective multi-target molecules for various complex diseases, demonstrating robustness and generalization capability. In addition, molecular docking and pharmacophore mapping experiments demonstrate the drug-likeness properties and effectiveness of generated molecules potentially improve neuropsychiatric interventions. Furthermore, our model's generalizability is exemplified by a case study focusing on the multi-targeted drug design for breast cancer. As a broadly applicable solution for multiple targets, MTMol-GPT provides new insight into future directions to enhance potential complex disease therapeutics by generating high-quality multi-target molecules in drug discovery.
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Biología Computacional , Descubrimiento de Drogas , Simulación del Acoplamiento Molecular , Humanos , Biología Computacional/métodos , Descubrimiento de Drogas/métodos , Diseño de Fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Algoritmos , Aprendizaje Profundo , Aprendizaje AutomáticoRESUMEN
The detection of therapeutic peptides is a topic of immense interest in the biomedical field. Conventional biochemical experiment-based detection techniques are tedious and time-consuming. Computational biology has become a useful tool for improving the detection efficiency of therapeutic peptides. Most computational methods do not consider the deviation caused by noise. To improve the generalization performance of therapeutic peptide prediction methods, this work presents a sequence homology score-based deep fuzzy echo-state network with maximizing mixture correntropy (SHS-DFESN-MMC) model. Our method is compared with the existing methods on eight types of therapeutic peptide datasets. The model parameters are determined by 10 fold cross-validation on their training sets and verified by independent test sets. Across the 8 datasets, the average area under the receiver operating characteristic curve (AUC) values of SHS-DFESN-MMC are the highest on both the training (0.926) and independent sets (0.923).
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Lógica Difusa , Redes Neurales de la Computación , Péptidos , Biología Computacional/métodos , Humanos , Aprendizaje Profundo , Área Bajo la Curva , Curva ROC , AlgoritmosRESUMEN
In recent years, nanoscale detection has played an increasingly important role in the research on viruses, exosomes, small bacteria, and organelles. The small size and complex biological natures of these particles, with the smallest known virus particle measuring only 17 nm in diameter and exosomes ranging from 30 nm to 150 nm in size, pose challenges to the classical large-scale (typically micron-scale) characterization methods, which has become a major obstacle in the research. The emergence of nanoscale detection and analysis technologies has filled the gap of optical microscopy, a conventional technique in this field. These technologies enable the sensitive and robust detection of objects that exceed the lower limit of optical detection, revealing the molecular composition and biological roles simultaneously. Currently, several commercialized instruments based on nanotechnology have emerged, providing complete single-particle detection solutions and achieving unique functionality based on their respective technological advantages. However, it is inevitable that these technologies have limitations in terms of application and detection capabilities, as they continue to evolve. This paper offers a thorough overview of the principles, advantages, limitations, and future development trends of several mainstream commercial instruments, aiming to serve researchers in selecting and utilizing these technologies.
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Nanopartículas , Nanotecnología , Nanopartículas/química , Nanotecnología/métodos , Exosomas , Virus/aislamiento & purificación , Tamaño de la PartículaRESUMEN
Pseudouridine is a type of abundant RNA modification that is seen in many different animals and is crucial for a variety of biological functions. Accurately identifying pseudouridine sites within the RNA sequence is vital for the subsequent study of various biological mechanisms of pseudouridine. However, the use of traditional experimental methods faces certain challenges. The development of fast and convenient computational methods is necessary to accurately identify pseudouridine sites from RNA sequence information. To address this, we introduce a novel pseudouridine site prediction model called PseU-KeMRF, which can identify pseudouridine sites in three species, H. sapiens, S. cerevisiae, and M. musculus. Through comprehensive analysis, we selected four RNA coding schemes, including binary feature, position-specific trinucleotide propensity based on single strand (PSTNPss), nucleotide chemical property (NCP) and pseudo k-tuple composition (PseKNC). Then the support vector machine-recursive feature elimination (SVM-RFE) method was used for feature selection and the feature subset was optimized. Finally, the best feature subsets are input into the kernel based on multinomial random forests (KeMRF) classifier for cross-validation and independent testing. As a new classification method, compared with the traditional random forest, KeMRF not only improves the node splitting process of decision tree construction based on multinomial distribution, but also combines the easy to interpret kernel method for prediction, which makes the classification performance better. Our results indicate superior predictive performance of PseU-KeMRF over other existing models. On the three species' training datasets, the testing accuracy of PseU-KeMRF was 0.66%, 3.66%, and 2.76% higher, respectively, than the best available methods. Moreover, PseU-KeMRF's accuracy on independent testing datasets was 15.15% and 11.0% higher, respectively, than the best available methods. The above results can prove that PseU-KeMRF is a highly competitive predictive model that can successfully identify pseudouridine sites in RNA sequences.
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Pseudouridine is an RNA modification that is widely distributed in both prokaryotes and eukaryotes, and plays a critical role in numerous biological activities. Despite its importance, the precise identification of pseudouridine sites through experimental approaches poses significant challenges, requiring substantial time and resources.Therefore, there is a growing need for computational techniques that can reliably and quickly identify pseudouridine sites from vast amounts of RNA sequencing data. In this study, we propose fuzzy kernel evidence Random Forest (FKeERF) to identify pseudouridine sites. This method is called PseU-FKeERF, which demonstrates high accuracy in identifying pseudouridine sites from RNA sequencing data. The PseU-FKeERF model selected four RNA feature coding schemes with relatively good performance for feature combination, and then input them into the newly proposed FKeERF method for category prediction. FKeERF not only uses fuzzy logic to expand the original feature space, but also combines kernel methods that are easy to interpret in general for category prediction. Both cross-validation tests and independent tests on benchmark datasets have shown that PseU-FKeERF has better predictive performance than several state-of-the-art methods. This new method not only improves the accuracy of pseudouridine site identification, but also provides a certain reference for disease control and related drug development in the future.
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Seudouridina , Bosques Aleatorios , Seudouridina/genética , ARN/genética , Secuencia de BasesRESUMEN
The accurate identification of drug-protein interactions (DPIs) is crucial in drug development, especially concerning G protein-coupled receptors (GPCRs), which are vital targets in drug discovery. However, experimental validation of GPCR-drug pairings is costly, prompting the need for accurate predictive methods. To address this, we propose MFD-GDrug, a multimodal deep learning model. Leveraging the ESM pretrained model, we extract protein features and employ a CNN for protein feature representation. For drugs, we integrated multimodal features of drug molecular structures, including three-dimensional features derived from Mol2vec and the topological information of drug graph structures extracted through Graph Convolutional Neural Networks (GCN). By combining structural characterizations and pretrained embeddings, our model effectively captures GPCR-drug interactions. Our tests on leading GPCR-drug interaction datasets show that MFD-GDrug outperforms other methods, demonstrating superior predictive accuracy.
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Aprendizaje Profundo , Interacciones Farmacológicas , Desarrollo de Medicamentos , Descubrimiento de Drogas , Redes Neurales de la ComputaciónRESUMEN
Rare variants contribute significantly to the genetic causes of complex traits, as they can have much larger effects than common variants and account for much of the missing heritability in genome-wide association studies. The emergence of UK Biobank scale datasets and accurate gene-level rare variant-trait association testing methods have dramatically increased the number of rare variant associations that have been detected. However, no systematic collection of these associations has been carried out to date, especially at the gene level. To address the issue, we present the Rare Variant Association Repository (RAVAR), a comprehensive collection of rare variant associations. RAVAR includes 95 047 high-quality rare variant associations (76186 gene-level and 18 861 variant-level associations) for 4429 reported traits which are manually curated from 245 publications. RAVAR is the first resource to collect and curate published rare variant associations in an interactive web interface with integrated visualization, search, and download features. Detailed gene and SNP information are provided for each association, and users can conveniently search for related studies by exploring the EFO tree structure and interactive Manhattan plots. RAVAR could vastly improve the accessibility of rare variant studies. RAVAR is freely available for all users without login requirement at http://www.ravar.bio.
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Bases de Datos Genéticas , Variación Genética , Estudio de Asociación del Genoma Completo , Estudio de Asociación del Genoma Completo/métodos , Herencia Multifactorial , FenotipoRESUMEN
The accurate prediction of drug-target affinity (DTA) is a crucial step in drug discovery and design. Traditional experiments are very expensive and time-consuming. Recently, deep learning methods have achieved notable performance improvements in DTA prediction. However, one challenge for deep learning-based models is appropriate and accurate representations of drugs and targets, especially the lack of effective exploration of target representations. Another challenge is how to comprehensively capture the interaction information between different instances, which is also important for predicting DTA. In this study, we propose AttentionMGT-DTA, a multi-modal attention-based model for DTA prediction. AttentionMGT-DTA represents drugs and targets by a molecular graph and binding pocket graph, respectively. Two attention mechanisms are adopted to integrate and interact information between different protein modalities and drug-target pairs. The experimental results showed that our proposed model outperformed state-of-the-art baselines on two benchmark datasets. In addition, AttentionMGT-DTA also had high interpretability by modeling the interaction strength between drug atoms and protein residues. Our code is available at https://github.com/JK-Liu7/AttentionMGT-DTA.
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Benchmarking , Descubrimiento de DrogasRESUMEN
OBJECTIVE: Postoperative delirium (POD) is a common postoperative complication in elderly patients, especially those undergoing cardiac surgery, which seriously affects the short- and long-term prognosis of patients. Early identification of risk factors for the development of POD can help improve the perioperative management of surgical patients. In the present study, five machine learning models were developed to predict patients at high risk of delirium after cardiac surgery and their performance was compared. METHODS: A total of 367 patients who underwent cardiac surgery were retrospectively included in this study. Using single-factor analysis, 21 risk factors for POD were selected for inclusion in machine learning. The dataset was divided using 10-fold cross-validation for model training and testing. Five machine learning models (random forest (RF), support vector machine (SVM), radial based kernel neural network (RBFNN), K-nearest neighbour (KNN), and Kernel ridge regression (KRR)) were compared using area under the receiver operating characteristic curve (AUC-ROC), accuracy (ACC), sensitivity (SN), specificity (SPE), and Matthews coefficient (MCC). RESULTS: Among 367 patients, 105 patients developed POD, the incidence of delirium was 28.6 %. Among the five ML models, RF had the best performance in ACC (87.99 %), SN (69.27 %), SPE (95.38 %), MCC (70.00 %) and AUC (0.9202), which was far superior to the other four models. CONCLUSION: Delirium is common in patients after cardiac surgery. This analysis confirms the importance of the computational ML models in predicting the occurrence of delirium after cardiac surgery, especially the outstanding performance of the RF model, which has practical clinical applications for early identification of patients at risk of developing POD.
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Procedimientos Quirúrgicos Cardíacos , Delirio del Despertar , Anciano , Humanos , Estudios Retrospectivos , Complicaciones Posoperatorias , Aprendizaje AutomáticoRESUMEN
Development of robust and effective strategies for synthesizing new compounds, drug targeting and constructing GEnome-scale Metabolic models (GEMs) requires a deep understanding of the underlying biological processes. A critical step in achieving this goal is accurately identifying the categories of pathways in which a compound participated. However, current machine learning-based methods often overlook the multifaceted nature of compounds, resulting in inaccurate pathway predictions. Therefore, we present a novel framework on Multi-View Multi-Label Learning for Metabolic Pathway Inference, hereby named MVML-MPI. First, MVML-MPI learns the distinct compound representations in parallel with corresponding compound encoders to fully extract features. Subsequently, we propose an attention-based mechanism that offers a fusion module to complement these multi-view representations. As a result, MVML-MPI accurately represents and effectively captures the complex relationship between compounds and metabolic pathways and distinguishes itself from current machine learning-based methods. In experiments conducted on the Kyoto Encyclopedia of Genes and Genomes pathways dataset, MVML-MPI outperformed state-of-the-art methods, demonstrating the superiority of MVML-MPI and its potential to utilize the field of metabolic pathway design, which can aid in optimizing drug-like compounds and facilitating the development of GEMs. The code and data underlying this article are freely available at https://github.com/guofei-tju/MVML-MPI. Contact: jtang@cse.sc.edu, guofei@csu.edu.com or wuxi_dyj@csj.uestc.edu.cn.
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Aprendizaje Automático , Redes y Vías MetabólicasRESUMEN
Protein sequence classification is a crucial research field in bioinformatics, playing a vital role in facilitating functional annotation, structure prediction, and gaining a deeper understanding of protein function and interactions. With the rapid development of high-throughput sequencing technologies, a vast amount of unknown protein sequence data is being generated and accumulated, leading to an increasing demand for protein classification and annotation. Existing machine learning methods still have limitations in protein sequence classification, such as low accuracy and precision of classification models, rendering them less valuable in practical applications. Additionally, these models often lack strong generalization capabilities and cannot be widely applied to various types of proteins. Therefore, accurately classifying and predicting proteins remains a challenging task. In this study, we propose a protein sequence classifier called Multi-Laplacian Regularized Random Vector Functional Link (MLapRVFL). By incorporating Multi-Laplacian and L2,1-norm regularization terms into the basic Random Vector Functional Link (RVFL) method, we effectively improve the model's generalization performance, enhance the robustness and accuracy of the classification model. The experimental results on two commonly used datasets demonstrate that MLapRVFL outperforms popular machine learning methods and achieves superior predictive performance compared to previous studies. In conclusion, the proposed MLapRVFL method makes significant contributions to protein sequence prediction.
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Aprendizaje Automático , Proteínas , Secuencia de Aminoácidos , Proteínas/genética , AlgoritmosRESUMEN
It is widely recognized that inequalities in social status cause inequalities in health. Women in a family often directly influence three generations-women themselves, their children and their parents -yet the effect of women's family status on their own health status and that of the two generations before and after is not clear. Taking data from the China Family Panel Studies, this study used an ordered response model to investigate the effect of childbearing-age women's family status on the health status of three generations. The results showed that increases in childbearing-age women's family status improved the health status of the women themselves and their children. Unlike previous studies, however, we found that higher family status did not improve parents' health status but decreased it. The mechanism analysis indicated that women's family status influenced the health status of three generations through economic conditions, resource allocation, and child discipline. The results held after robustness testing. Our findings contribute to knowledge in related fields and provide theoretical support for policies that empower women.
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Padres , Derechos de la Mujer , Niño , Femenino , Humanos , Factores Socioeconómicos , China , Estado de SaludRESUMEN
Adverse drug reactions include side effects, allergic reactions, and secondary infections. Severe adverse reactions can cause cancer, deformity, or mutation. The monitoring of drug side effects is an important support for post marketing safety supervision of drugs, and an important basis for revising drug instructions. Its purpose is to timely detect and control drug safety risks. Traditional methods are time-consuming. To accelerate the discovery of side effects, we propose a machine learning based method, called correntropy-loss based matrix factorization with neural tangent kernel (CLMF-NTK), to solve the prediction of drug side effects. Our method and other computational methods are tested on three benchmark datasets, and the results show that our method achieves the best predictive performance.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias , Humanos , Aprendizaje Automático , Neoplasias/genética , Benchmarking , AlgoritmosRESUMEN
In recent years, research in the field of bioinformatics has focused on predicting the raw sequences of proteins, and some scholars consider DNA-binding protein prediction as a classification task. Many statistical and machine learning-based methods have been widely used in DNA-binding proteins research. The aforementioned methods are indeed more efficient than those based on manual classification, but there is still room for improvement in terms of prediction accuracy and speed. In this study, researchers used Average Blocks, Discrete Cosine Transform, Discrete Wavelet Transform, Global encoding, Normalized Moreau-Broto Autocorrelation and Pseudo position-specific scoring matrix to extract evolutionary features. A dynamic deep network based on lifelong learning architecture was then proposed in order to fuse six features and thus allow for more efficient classification of DNA-binding proteins. The multi-feature fusion allows for a more accurate description of the desired protein information than single features. This model offers a fresh perspective on the dichotomous classification problem in bioinformatics and broadens the application field of lifelong learning. The researchers ran trials on three datasets and contrasted them with other classification techniques to show the model's effectiveness in this study. The findings demonstrated that the model used in this research was superior to other approaches in terms of single-sample specificity (81.0%, 83.0%) and single-sample sensitivity (82.4%, 90.7%), and achieves high accuracy on the benchmark dataset (88.4%, 80.0%, and 76.6%).
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Proteínas de Unión al ADN , Aprendizaje Automático , Unión Proteica , Proteínas de Unión al ADN/metabolismo , Biología Computacional/métodos , ADNRESUMEN
DNA-binding proteins (DBPs) play a critical role in the development of drugs for treating genetic diseases and in DNA biology research. It is essential for predicting DNA-binding proteins more accurately and efficiently. In this paper, a Laplacian Local Kernel Alignment-based Restricted Kernel Machine (LapLKA-RKM) is proposed to predict DBPs. In detail, we first extract features from the protein sequence using six methods. Second, the Radial Basis Function (RBF) kernel function is utilized to construct pre-defined kernel metrics. Then, these metrics are combined linearly by weights calculated by LapLKA. Finally, the fused kernel is input to RKM for training and prediction. Independent tests and leave-one-out cross-validation were used to validate the performance of our method on a small dataset and two large datasets. Importantly, we built an online platform to represent our model, which is now freely accessible via http://8.130.69.121:8082/.
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Algoritmos , Proteínas de Unión al ADN , Máquina de Vectores de SoporteRESUMEN
Vesicular transport proteins participate in various biological processes and play a significant role in the movement of substances within cells. These proteins are associated with numerous human diseases, making their identification particularly important. In this study, we developed a novel strategy for accurately identifying vesicular transport proteins. We developed a novel multi-view classifier called graph-regularized k-local hyperplane distance nearest neighbor model (HSIC-GHKNN), which combines the Hilbert-Schmidt independence criterion (HSIC)-based multi-view learning method with a local hyperplane distance nearest-neighbor classifier. We first extracted protein evolution information using two feature extraction methods, pseudo-position-specific scoring matrix (PsePSSM) and AATP, and addressed dataset imbalance using the Edited Nearest Neighbors (ENN) algorithm. Subsequently, we employed a local hyperplane distance nearest-neighbor classifier for each view identification and added an HSIC term to maintain independence between views. We then assessed the performance of our identification strategy and analyzed the PsePSSM and AATP feature sets to determine the influencing factors of the classification results. The experimental results demonstrate that the accurate and Matthew correlation coefficients of our strategy on the independent test set are 85.8 % and 0.548, respectively. Our approach outperformed existing methods in most evaluation metrics. In addition, the proposed multi-view classification model can easily be applied to similar identification tasks.
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Algoritmos , Proteínas de Transporte Vesicular , HumanosRESUMEN
High-fat diet (HFD)-induced insulin resistance (IR) in skeletal muscle is often accompanied by mitochondrial dysfunction and oxidative stress. Boosting nicotinamide adenine dinucleotide (NAD) using nicotinamide riboside (NR) can effectively decrease oxidative stress and increase mitochondrial function. However, whether NR can ameliorate IR in skeletal muscle is still inconclusive. We fed male C57BL/6J mice with an HFD (60% fat) ± 400 mg/kg·bw NR for 24 weeks. C2C12 myotube cells were treated with 0.25 mM palmitic acid (PA) ± 0.5 mM NR for 24 h. Indicators for IR and mitochondrial dysfunction were analyzed. NR treatment alleviated IR in HFD-fed mice with regard to improved glucose tolerance and a remarkable decrease in the levels of fasting blood glucose, fasting insulin and HOMA-IR index. NR-treated HFD-fed mice also showed improved metabolic status regarding a significant reduction in body weight and lipid contents in serum and the liver. NR activated AMPK in the skeletal muscle of HFD-fed mice and PA-treated C2C12 myotube cells and upregulated the expression of mitochondria-related transcriptional factors and coactivators, thereby improving mitochondrial function and alleviating oxidative stress. Upon inhibiting AMPK using Compound C, NR lost its ability in enhancing mitochondrial function and protection against IR induced by PA. In summary, improving mitochondrial function through the activation of AMPK pathway in skeletal muscle may play an important role in the amelioration of IR using NR.