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Around 50 years ago, molecular biology opened the path to understand changes in forms, adaptations, complexity, or the basis of human diseases through myriads of reports on gene birth, gene duplication, gene expression regulation, and splicing regulation, among other relevant mechanisms behind gene function. Here, with the advent of big data and artificial intelligence (AI), we focus on an elusive and intriguing mechanism of gene function regulation, RNA editing, in which a single nucleotide from an RNA molecule is changed, with a remarkable impact in the increase of the complexity of the transcriptome and proteome. We present a new generation approach to assess the functional conservation of the RNA-editing targeting mechanism using two AI learning algorithms, random forest (RF) and bidirectional long short-term memory (biLSTM) neural networks with an attention layer. These algorithms, combined with RNA-editing data coming from databases and variant calling from same-individual RNA and DNA-seq experiments from different species, allowed us to predict RNA-editing events using both primary sequence and secondary structure. Then, we devised a method for assessing conservation or divergence in the molecular mechanisms of editing completely in silico: the cross-testing analysis. This novel method not only helps to understand the conservation of the editing mechanism through evolution but could set the basis for achieving a better understanding of the adenosine-targeting mechanism in other fields.
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Aprendizaje Automático , Edición de ARN , Humanos , Algoritmos , Simulación por Computador , Biología Computacional/métodos , Redes Neurales de la Computación , ARN/genética , ARN/metabolismoRESUMEN
An outstanding event related to the understanding of the physics of mechanical sensors occurred and was announced in 1954, exactly seventy years ago. This event was the discovery of the piezoresistive effect, which led to the development of semiconductor strain gauges with a sensitivity much higher than that obtained before in conventional metallic strain gauges. In turn, this motivated the subsequent development of the earliest micromachined silicon devices and the corresponding MEMS devices. The science and technology related to sensors has experienced noteworthy advances in the last decades, but the piezoresistive effect is still the main physical phenomenon behind many mechanical sensors, both commercial and in research models. On this 70th anniversary, this tutorial aims to explain the operating principle, subtypes, input-output characteristics, and limitations of the three main types of mechanical sensor: strain gauges, capacitive sensors, and piezoelectric sensors. These three sensor technologies are also compared with each other, highlighting the main advantages and disadvantages of each one.
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This article proposes and experimentally characterizes two implementations of a novel front-end circuit for three-wire connected resistive sensors with a wire-resistance compensation. The first implementation relies on two twin diodes, whereas the second on a switch; in both cases, those devices are non-remote (i.e., they are placed at the circuit end). The two circuit proposals have a square-wave input excitation so that a constant current with the two polarities is alternatively generated. Then, depending on that polarity, the current goes through either the sensor and the wire parasitic resistances or just the parasitic resistances. This generates a square-wave bipolar output signal whose average value, which is obtained by a low-pass filter, is proportional to the sensor resistance and only depends on the mismatch between two of the three wire resistances involved. Experimental tests applied to resistances related to a Pt100 thermal sensor show a remarkable linearity. For example, the switch-based front-end circuit offers a non-linearity error lower than 0.01% full-scale span, and this is practically insensitive to both the presence and the mismatch between the wire resistances.
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We have produced RNA sequencing data for 53 primary cells from different locations in the human body. The clustering of these primary cells reveals that most cells in the human body share a few broad transcriptional programs, which define five major cell types: epithelial, endothelial, mesenchymal, neural, and blood cells. These act as basic components of many tissues and organs. Based on gene expression, these cell types redefine the basic histological types by which tissues have been traditionally classified. We identified genes whose expression is specific to these cell types, and from these genes, we estimated the contribution of the major cell types to the composition of human tissues. We found this cellular composition to be a characteristic signature of tissues and to reflect tissue morphological heterogeneity and histology. We identified changes in cellular composition in different tissues associated with age and sex, and found that departures from the normal cellular composition correlate with histological phenotypes associated with disease.
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Transcripción Genética , Línea Celular , Células Endoteliales/metabolismo , Células Epiteliales/metabolismo , Femenino , Perfilación de la Expresión Génica , Ginecomastia/genética , Ginecomastia/metabolismo , Humanos , Masculino , Mesodermo/citología , Mesodermo/metabolismo , Neoplasias/genética , Especificidad de Órganos , Análisis de Secuencia de ARNRESUMEN
In this article, a novel front-end circuit for remote two-wire resistive sensors that is insensitive to the wire resistances is proposed and experimentally characterized. The circuit relies on an OpAmp-based current source with a square-wave excitation, two twin diodes in the feedback path, and a low-pass filter at the output. Using such a circuit topology, the output is a DC voltage proportional to the sensor resistance and independent of the wire resistances. A prototype was built measuring resistances that correspond to a Pt100 thermal sensor and with different values of wire resistance. The experimental results show that the output voltage is almost insensitive to both the wire resistances and their mismatch, with a relative error (with respect to the case with null parasitic resistance) in the range of 0.01-0.03% Full-Scale Span (FSS). In addition, the proposed circuit shows a remarkable linearity (around 0.01% FSS), and again this is independent of the presence and also of the mismatch of the wire resistances.
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A new sensor topology meant to extract figures of merit of radio-frequency analog integrated circuits (RF-ICs) was experimentally validated. Implemented in a standard 0.35 µm complementary metal-oxide-semiconductor (CMOS) technology, it comprised two blocks: a single metal-oxide-semiconductor (MOS) transistor acting as temperature transducer, which was placed near the circuit to monitor, and an active band-pass filter amplifier. For validation purposes, the temperature sensor was integrated with a tuned radio-frequency power amplifier (420 MHz) and MOS transistors acting as controllable dissipating devices. First, using the MOS dissipating devices, the performance and limitations of the different blocks that constitute the temperature sensor were characterized. Second, by using the heterodyne technique (applying two nearby tones) to the power amplifier (PA) and connecting the sensor output voltage to a low-cost AC voltmeter, the PA's output power and its central frequency were monitored. As a result, this topology resulted in a low-cost approach, with high linearity and sensitivity, for RF-IC testing and variability monitoring.
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BACKGROUND: The necessity to analyze medium-throughput data in epidemiological studies with small sample size, particularly when studying biomedical data may hinder the use of classical statistical methods. Support vector machines (SVM) models can be successfully applied in this setting because they are a powerful tool to analyze data with large number of predictors and limited sample size, especially when handling binary outcomes. However, biomedical research often involves analysis of time-to-event outcomes and has to account for censoring. Methods to handle censored data in the SVM framework can be divided into two classes: those based on support vector regression (SVR) and those based on binary classification. Methods based on SVR seem to be suboptimal to handle sparse data and yield results comparable to Cox proportional hazards model and kernel Cox regression. The limited work dedicated to assess methods based on of SVM for binary classification has been based on SVM learning using privileged information and SVM with uncertain classes. RESULTS: This paper proposes alternative methods and extensions within the binary classification framework, specifically, a conditional survival approach for weighting censored observations and a semi-supervised SVM with local invariances. Using simulation studies and some real datasets, we evaluate those two methods and compare them with a weighted SVM model, SVM extensions found in the literature, kernel Cox regression and Cox model. CONCLUSIONS: Our proposed methods perform generally better under a wide variety of realistic scenarios about the structure of biomedical data. Specifically, the local invariances method using the conditional survival approach is the most robust method under different scenarios and is a good approach to consider as an alternative to other time-to-event methods. When analysing real data is a method to be considered and recommended since outperforms other methods in proportional and non-proportional scenarios and sparse data, which is something usual in biomedical data and biomarkers analysis.
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Máquina de Vectores de Soporte , Análisis de Supervivencia , Humanos , Modelos de Riesgos ProporcionalesRESUMEN
An amendment to this paper has been published and can be accessed via the original article.
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This paper proposes a compact Thévenin model for a rectenna. This model is then applied to design a high-efficiency radio frequency harvester with a maximum power point tracker (MPPT). The rectenna under study consists of an L-matching network and a half-wave rectifier. The derived model is simpler and more compact than those suggested so far in the literature and includes explicit expressions of the Thévenin voltage (Voc) and resistance and of the power efficiency related with the parameters of the rectenna. The rectenna was implemented and characterized from -30 to -10 dBm at 808 MHz. Experimental results agree with the proposed model, showing a linear currentâ»voltage relationship as well as a maximum efficiency at Voc/2, in particular 60% at -10 dBm, which is a remarkable value. An MPPT was also used at the rectenna output in order to automatically work at the maximum efficiency point, with an overall efficiency near 50% at -10 dBm. Further tests were performed using a nearby transmitting antenna for powering a sensor node with a power consumption of 4.2 µW.
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This paper proposes a microcontroller-based measurement system to detect and confirm the presence of a subject in a chair. The system relies on a single Force Sensing Resistor (FSR), which is arranged in the seat of the chair, that undergoes a sudden resistance change when a subject/object is seated/placed over the chair. In order to distinguish between a subject and an inanimate object, the system also monitors small-signal variations of the FSR resistance caused by respiration. These resistance variations are then directly measured by a low-cost general-purpose microcontroller unit (MCU) without using either an analogue processing stage or an analogue-to-digital converter. Two versions of such a MCU-based circuit are presented: one to prove the concept of the measurement, and another with a smart wake-up (generated by the sudden resistance change) intended to reduce the energy consumption. The feasibility of the proposed measurement system is experimentally demonstrated with subjects of different weight sitting at different postures, and also with objects of different weight. The MCU-based circuit with a smart wake-up shows a standby current consumption of 800 nA, and requires an energy of 125 µJ to carry out the measurement after the wake-up.
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BACKGROUND: Support vector machines (SVM) are a powerful tool to analyze data with a number of predictors approximately equal or larger than the number of observations. However, originally, application of SVM to analyze biomedical data was limited because SVM was not designed to evaluate importance of predictor variables. Creating predictor models based on only the most relevant variables is essential in biomedical research. Currently, substantial work has been done to allow assessment of variable importance in SVM models but this work has focused on SVM implemented with linear kernels. The power of SVM as a prediction model is associated with the flexibility generated by use of non-linear kernels. Moreover, SVM has been extended to model survival outcomes. This paper extends the Recursive Feature Elimination (RFE) algorithm by proposing three approaches to rank variables based on non-linear SVM and SVM for survival analysis. RESULTS: The proposed algorithms allows visualization of each one the RFE iterations, and hence, identification of the most relevant predictors of the response variable. Using simulation studies based on time-to-event outcomes and three real datasets, we evaluate the three methods, based on pseudo-samples and kernel principal component analysis, and compare them with the original SVM-RFE algorithm for non-linear kernels. The three algorithms we proposed performed generally better than the gold standard RFE for non-linear kernels, when comparing the truly most relevant variables with the variable ranks produced by each algorithm in simulation studies. Generally, the RFE-pseudo-samples outperformed the other three methods, even when variables were assumed to be correlated in all tested scenarios. CONCLUSIONS: The proposed approaches can be implemented with accuracy to select variables and assess direction and strength of associations in analysis of biomedical data using SVM for categorical or time-to-event responses. Conducting variable selection and interpreting direction and strength of associations between predictors and outcomes with the proposed approaches, particularly with the RFE-pseudo-samples approach can be implemented with accuracy when analyzing biomedical data. These approaches, perform better than the classical RFE of Guyon for realistic scenarios about the structure of biomedical data.
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Algoritmos , Biomarcadores de Tumor/genética , Gráficos por Computador , Cirrosis Hepática Biliar/mortalidad , Neoplasias Pulmonares/mortalidad , Linfoma de Células B Grandes Difuso/mortalidad , Máquina de Vectores de Soporte , Humanos , Cirrosis Hepática Biliar/genética , Neoplasias Pulmonares/genética , Linfoma de Células B Grandes Difuso/genética , Tasa de SupervivenciaRESUMEN
This paper evaluates the performance of direct interface circuits (DIC), where the sensor is directly connected to a microcontroller, when a resistive sensor subjected to dynamic changes is measured. The theoretical analysis provides guidelines for the selection of the components taking into account both the desired resolution and the bandwidth of the input signal. Such an analysis reveals that there is a trade-off between the sampling frequency and the resolution of the measurement, and this depends on the selected value of the capacitor that forms the RC circuit together with the sensor resistance. This performance is then experimentally proved with a DIC measuring a magnetoresistive sensor exposed to a magnetic field of different frequencies, amplitudes, and waveforms. A sinusoidal magnetic field up to 1 kHz can be monitored with a resolution of eight bits and a sampling frequency of around 10 kSa/s. If a higher resolution is desired, the sampling frequency has to be lower, thus limiting the bandwidth of the dynamic signal under measurement. The DIC is also applied to measure an electrocardiogram-type signal and its QRS complex is well identified, which enables the estimation, for instance, of the heart rate.
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BACKGROUND: Pathway expression is multivariate in nature. Thus, from a statistical perspective, to detect differentially expressed pathways between two conditions, methods for inferring differences between mean vectors need to be applied. Maximum mean discrepancy (MMD) is a statistical test to determine whether two samples are from the same distribution, its implementation being greatly simplified using the kernel method. RESULTS: An MMD-based test successfully detected the differential expression between two conditions, specifically the expression of a set of genes involved in certain fatty acid metabolic pathways. Furthermore, we exploited the ability of the kernel method to integrate data and successfully added hepatic fatty acid levels to the test procedure. CONCLUSION: MMD is a non-parametric test that acquires several advantages when combined with the kernelization of data: 1) the number of variables can be greater than the sample size; 2) omics data can be integrated; 3) it can be applied not only to vectors, but to strings, sequences and other common structured data types arising in molecular biology.
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Algoritmos , Biología Computacional/métodos , Expresión Génica , Animales , Dieta , Ácidos Grasos/metabolismo , Genómica , Hígado/metabolismo , Metabolómica , Ratones , Ratones Noqueados , Aceites de Plantas/química , Aceites de Plantas/metabolismo , Aceite de GirasolRESUMEN
Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.
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Adipoquinas/líquido cefalorraquídeo , Enfermedades Desmielinizantes/líquido cefalorraquídeo , Enfermedades Desmielinizantes/diagnóstico , Lectinas/líquido cefalorraquídeo , Adipoquinas/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Encéfalo/metabolismo , Encéfalo/patología , Proteína 1 Similar a Quitinasa-3 , Femenino , Estudios de Seguimiento , Humanos , Lectinas/biosíntesis , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Long noncoding RNAs (lncRNAs) are emerging as important regulators of developmental pathways. However, their roles in human cardiac precursor cell (CPC) remain unexplored. To characterize the long noncoding transcriptome during human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs isolated from the human fetal heart and identified 570 lncRNAs that were modulated during cardiac differentiation. Many of these were associated with active cardiac enhancer and super enhancers (SE) with their expression being correlated with proximal cardiac genes. One of the most upregulated lncRNAs was a SE-associated lncRNA that was named CARMEN, (CAR)diac (M)esoderm (E)nhancer-associated (N)oncoding RNA. CARMEN exhibits RNA-dependent enhancing activity and is upstream of the cardiac mesoderm-specifying gene regulatory network. Interestingly, CARMEN interacts with SUZ12 and EZH2, two components of the polycomb repressive complex 2 (PRC2). We demonstrate that CARMEN knockdown inhibits cardiac specification and differentiation in cardiac precursor cells independently of MIR-143 and -145 expression, two microRNAs located proximal to the enhancer sequences. Importantly, CARMEN expression was activated during pathological remodeling in the mouse and human hearts, and was necessary for maintaining cardiac identity in differentiated cardiomyocytes. This study demonstrates therefore that CARMEN is a crucial regulator of cardiac cell differentiation and homeostasis.
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Tipificación del Cuerpo/genética , Diferenciación Celular/genética , Corazón/embriología , Homeostasis/genética , ARN Largo no Codificante/metabolismo , Animales , Linaje de la Célula/genética , Elementos de Facilitación Genéticos/genética , Proteína Potenciadora del Homólogo Zeste 2 , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Miocardio/patología , Complejo Represivo Polycomb 2/metabolismo , ARN Largo no Codificante/genética , Células Madre/citología , Transcriptoma/genéticaRESUMEN
High-throughput technologies have generated vast amounts of omic data. It is a consensus that the integration of diverse omics sources improves predictive models and biomarker discovery. However, managing multiple omics data poses challenges such as data heterogeneity, noise, high-dimensionality and missing data, especially in block-wise patterns. This study addresses the challenges of high dimensionality and block-wise missing data through a regularization and constrained-based approach. The methodology is implemented in the R package bwm for binary and continuous response variables, and applied to breast cancer and exposome multi-omics datasets, achieving strong performance even in scenarios with missing data present in all omics. In binary classification task, our proposed model achieves accuracy in the range of 86% to 92%, and F1 in the range of 68% to 79%. And, in regression task the correlation between true and predicted responses is in the range of 72% to 76%. However, there is a slight decline in performance metrics as the percentage of missing data increases. In scenarios where block-wise missing data affects multiple omics, the model performance actually surpasses that of scenarios where missing data is present in only one omics. One possible explanation for this might be that the other scenarios introduce a greater diversity of observation profiles, leading to a more robust model. Depending on the specific omics being studied, there is greater consistency in feature selection when comparing block-wise missing data scenarios.
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Neoplasias de la Mama , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Genómica/métodos , Algoritmos , Femenino , MultiómicaRESUMEN
The increasing availability of multidimensional phenotypic data in large cohorts of genotyped individuals requires efficient methods to identify genetic effects on multiple traits. Permutational multivariate analysis of variance (PERMANOVA) offers a powerful non-parametric approach. However, it relies on permutations to assess significance, which hinders the analysis of large datasets. Here, we derive the limiting null distribution of the PERMANOVA test statistic, providing a framework for the fast computation of asymptotic p values. Our asymptotic test presents controlled type I error and high power, often outperforming parametric approaches. We illustrate its applicability in the context of QTL mapping and GWAS.
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Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Fenotipo , Genotipo , Mapeo Cromosómico , Modelos GenéticosRESUMEN
Understanding the consequences of individual transcriptome variation is fundamental to deciphering human biology and disease. We implement a statistical framework to quantify the contributions of 21 individual traits as drivers of gene expression and alternative splicing variation across 46 human tissues and 781 individuals from the Genotype-Tissue Expression project. We demonstrate that ancestry, sex, age, and BMI make additive and tissue-specific contributions to expression variability, whereas interactions are rare. Variation in splicing is dominated by ancestry and is under genetic control in most tissues, with ribosomal proteins showing a strong enrichment of tissue-shared splicing events. Our analyses reveal a systemic contribution of types 1 and 2 diabetes to tissue transcriptome variation with the strongest signal in the nerve, where histopathology image analysis identifies novel genes related to diabetic neuropathy. Our multi-tissue and multi-trait approach provides an extensive characterization of the main drivers of human transcriptome variation in health and disease.
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Long non-coding RNAs (lncRNAs) are involved in numerous biological processes and are pivotal mediators of the immune response, yet little is known about their properties at the single-cell level. Here, we generate a multi-tissue bulk RNAseq dataset from Ebola virus (EBOV) infected and not-infected rhesus macaques and identified 3979 novel lncRNAs. To profile lncRNA expression dynamics in immune circulating single-cells during EBOV infection, we design a metric, Upsilon, to estimate cell-type specificity. Our analysis reveals that lncRNAs are expressed in fewer cells than protein-coding genes, but they are not expressed at lower levels nor are they more cell-type specific when expressed in the same number of cells. In addition, we observe that lncRNAs exhibit similar changes in expression patterns to those of protein-coding genes during EBOV infection, and are often co-expressed with known immune regulators. A few lncRNAs change expression specifically upon EBOV entry in the cell. This study sheds light on the differential features of lncRNAs and protein-coding genes and paves the way for future single-cell lncRNA studies.
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Ebolavirus , Fiebre Hemorrágica Ebola , ARN Largo no Codificante , Animales , Fiebre Hemorrágica Ebola/genética , ARN Largo no Codificante/genética , Macaca mulatta , Ebolavirus/genética , Internalización del VirusRESUMEN
The aim of this study was to assess the effects of a mixture of four dietary fibers on obese rats. Four groups of male Wistar rats were fed with either standard chow (STD) or cafeteria diet (CAF) and were orally supplemented with either fibre mixture (2 g kg-1 of body weight) (STD+F or CAF+F groups) or vehicle (STD+VH or CAF+VH groups). We studied a wide number of biometric, biochemical, transcriptomic, metagenomic and metabolomic variables and applied an integrative multivariate approach based on multiple factor analysis and Pearson's correlation analysis. A significant reduction in body weight, adiposity, HbA1c and HDL-cholesterol serum levels, and colon MPO activity was observed, whereas cecal weight and small intestine length:weight ratio were significantly increased in F-treated groups compared to control animals. CAF+F rats displayed a significant enhancement in energy expenditure, fat oxidation and fresh stool weight, and a significant reduction in adiponectin and LPS serum levels, compared to control group. Animals in STD+F group showed reduced serum LDL-cholesterol levels and a significant reduction in total cholesterol levels in the liver compared to STF+VH group. The intervention effect was reflected at the metabolomic (i.e., production of short-chain fatty acids, phenolic acids, and amino acids), metagenomic (i.e., modulation of Ruminococcus and Lactobacillus genus) and transcriptomic (i.e., expression of tight junctions and proteolysis) levels. Altogether, our integrative multi-omics approach highlights the potential of supplementation with a mixture of fibers to ameliorate the impairments triggered by obesity in terms of adiposity, metabolic profile, and intestinal health.