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The circadian clock system coordinates metabolic, physiological, and behavioral functions across a 24-h cycle, crucial for adapting to environmental changes. Disruptions in circadian rhythms contribute to major metabolic pathologies like obesity and Type 2 diabetes. Understanding the regulatory mechanisms governing circadian control is vital for identifying therapeutic targets. It is well characterized that chromatin remodeling and 3D structure at genome regulatory elements contributes to circadian transcriptional cycles; yet the impact of rhythmic chromatin topology in metabolic disease is largely unexplored. In this study, we explore how the spatial configuration of the genome adapts to diet, rewiring circadian transcription and contributing to dysfunctional metabolism. We describe daily fluctuations in chromatin contacts between distal regulatory elements of metabolic control genes in livers from lean and obese mice and identify specific lipid-responsive regions recruiting the clock molecular machinery. Interestingly, under high-fat feeding, a distinct interactome for the clock-controlled gene Dbp strategically promotes the expression of distal metabolic genes including Fgf21. Alongside, new chromatin loops between regulatory elements from genes involved in lipid metabolism control contribute to their transcriptional activation. These enhancers are responsive to lipids through CEBPß, counteracting the circadian repressor REVERBa. Our findings highlight the intricate coupling of circadian gene expression to a dynamic nuclear environment under high-fat feeding, supporting a temporally regulated program of gene expression and transcriptional adaptation to diet.
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Cromatina , Relojes Circadianos , Ácidos Grasos , Hígado , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad , Animales , Cromatina/metabolismo , Cromatina/genética , Hígado/metabolismo , Ratones , Relojes Circadianos/genética , Obesidad/metabolismo , Obesidad/genética , Ácidos Grasos/metabolismo , Masculino , Dieta Alta en Grasa/efectos adversos , Ensamble y Desensamble de Cromatina , Ritmo Circadiano/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Metabolismo de los Lípidos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
Topological data analysis (TDA) is a recent approach for analyzing and interpreting complex data sets based on ideas a branch of mathematics called algebraic topology. TDA has proven useful to disentangle non-trivial data structures in a broad range of data analytics problems including the study of cardiovascular signals. Here, we aim to provide an overview of the application of TDA to cardiovascular signals and its potential to enhance the understanding of cardiovascular diseases and their treatment in the form of a literature or narrative review. We first introduce the concept of TDA and its key techniques, including persistent homology, Mapper, and multidimensional scaling. We then discuss the use of TDA in analyzing various cardiovascular signals, including electrocardiography, photoplethysmography, and arterial stiffness. We also discuss the potential of TDA to improve the diagnosis and prognosis of cardiovascular diseases, as well as its limitations and challenges. Finally, we outline future directions for the use of TDA in cardiovascular signal analysis and its potential impact on clinical practice. Overall, TDA shows great promise as a powerful tool for the analysis of complex cardiovascular signals and may offer significant insights into the understanding and management of cardiovascular diseases.
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Breast cancer encompasses a diverse array of subtypes, each exhibiting distinct clinical characteristics and treatment responses. Unraveling the underlying regulatory mechanisms that govern gene expression patterns in these subtypes is essential for advancing our understanding of breast cancer biology. Gene co-expression networks (GCNs) help us identify groups of genes that work in coordination. Previous research has revealed a marked reduction in the interaction of genes located on different chromosomes within GCNs for breast cancer, as well as for lung, kidney, and hematopoietic cancers. However, the reasons behind why genes on the same chromosome often co-express remain unclear. In this study, we investigate the role of transcription factors in shaping gene co-expression networks within the four main breast cancer subtypes: Luminal A, Luminal B, HER2+, and Basal, along with normal breast tissue. We identify communities within each GCN and calculate the transcription factors that may regulate these communities, comparing the results across different phenotypes. Our findings indicate that, in general, regulatory behavior is to a large extent similar among breast cancer molecular subtypes and even in healthy networks. This suggests that transcription factor motif usage does not fully determine long-range co-expression patterns. Specific transcription factor motifs, such as CCGGAAG, appear frequently across all phenotypes, even involving multiple highly connected transcription factors. Additionally, certain transcription factors exhibit unique actions in specific subtypes but with limited influence. Our research demonstrates that the loss of inter-chromosomal co-expression is not solely attributable to transcription factor regulation. Although the exact mechanism responsible for this phenomenon remains elusive, this work contributes to a better understanding of gene expression regulatory programs in breast cancer.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Factores de Transcripción/genética , Mama , Cromosomas , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: During the COVID-19 pandemic, the slope of the epidemic curve in Mexico City has been quite unstable. Changes in human activity led to changes in epidemic activity, hampering attempts at economic and general reactivation of the city. METHODS: We have predicted that where a fraction of the population above a certain threshold returns to the public space, the negative tendency of the epidemic curve will revert. Such predictions were based on modeling the reactivation of economic activity after lockdown using an epidemiological model resting upon a contact network of Mexico City derived from mobile device co-localization. We modeled scenarios with different proportions of the population returning to normalcy. Null models were built using the Jornada Nacional de Sana Distancia (the Mexican model of elective lockdown). There was a mobility reduction of 75% and no mandatory mobility restrictions. RESULTS: We found that a new peak of cases in the epidemic curve was very likely for scenarios in which more than 5% of the population rejoined the public space. The return of more than 50% of the population synchronously will unleash a magnitude similar to the one predicted with no mitigation strategies. By evaluating the tendencies of the epidemic dynamics, the number of new cases registered, hospitalizations, and recent deaths, we consider that reactivation following only elective measures may not be optimal under this scenario. CONCLUSIONS: Given the need to resume economic activities, we suggest alternative measures that minimize unnecessary contacts among people returning to the public space. We evaluated that "encapsulating" reactivated workers (that is, using measures to reduce the number of contacts beyond their influential community in the contact network) may allow reactivation of a more significant fraction of the population without compromising the desired tendency in the epidemic curve.
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COVID-19 , COVID-19/epidemiología , Control de Enfermedades Transmisibles , Humanos , México/epidemiología , Pandemias , SARS-CoV-2RESUMEN
OBJECTIVES: There is no consensus on how to evaluate inflammatory activity in Takayasu's arteritis (TAK). Here we compare biochemical tests and three clinical scores, which evaluate inflammatory activity (IA) in TAK, versus quantitative 18F-FDG PET/CT as the gold standard. METHODS: This prospective study included patients with TA diagnosed according to the American College of Rheumatology (ACR) criteria. IA was assessed through laboratory tests, clinical scores of the National Institute of Health (NIH), Dabague-Reyes (DR) and the Indian Takayasu Clinical Activity Score 2010 (ITAS2010), and the result of these assessments was compared against 18F-FDG PET/CT Standardised Uptake Values (SUVmax). RESULTS: A total of 35 patients were studied, 86% were women. SUVmax had positive correlations with acute phase reactants and DR and NIH. Agreement of 18F-FDG PET/CT was significant with erythrocyte sedimentation rate (ESR) and DR score. Receiver Operating Characteristic (ROC) curve analysis showed diagnostic value for inflammatory activity in ESR, DR and NIH scores, which had higher specificity when they were estimated with new cut-off points for the Mexican population. CONCLUSIONS: ESR and other phase reactants have good sensitivity but low specificity to evaluate IA in TAK when compared against 18F-FDG PET/CT. Among all the clinical scores, DR had the best diagnostic value, with strong potential as a clinical tool to define the inflammatory status in TAK patients when the study image is not available. However, in complex TAK cases with doubtful diagnosis after assessment by clinical scores or laboratory, 18F-FDG PET/CT remains mandatory.
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Fluorodesoxiglucosa F18 , Arteritis de Takayasu , Biomarcadores , Femenino , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , Estudios Prospectivos , Radiofármacos , Arteritis de Takayasu/diagnóstico por imagenRESUMEN
BACKGROUND: Around the world, there is a significant difference in the proportion of women with access to leadership in healthcare with respect to men. This article studies gender imbalance and wage gap in managerial, executive, and directive job positions at the Mexican National Institutes of Health. METHODS: Cohort data were described using a visual circular representation and modeled using a generalized linear model. Analysis of variance was used to assess model significance, and posterior Fisher's least significant differences were analyzed when appropriate. RESULTS: This study demonstrated that there is a gender imbalance distribution among the hierarchical position at the Mexican National Health Institutes and also exposed that the wage gap exists mainly in the (highest or lowest) ranks in hierarchical order. CONCLUSIONS: Since the majority of the healthcare workforce is female, Mexican women are still underrepresented in executive and directive management positions at national healthcare organizations.
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Personal Administrativo/estadística & datos numéricos , Liderazgo , Administración en Salud Pública/estadística & datos numéricos , Movilidad Laboral , Humanos , México , Salarios y Beneficios/estadística & datos numéricos , Distribución por SexoRESUMEN
Here, we introduce a class of Tensor Markov Fields intended as probabilistic graphical models from random variables spanned over multiplexed contexts. These fields are an extension of Markov Random Fields for tensor-valued random variables. By extending the results of Dobruschin, Hammersley and Clifford to such tensor valued fields, we proved that tensor Markov fields are indeed Gibbs fields, whenever strictly positive probability measures are considered. Hence, there is a direct relationship with many results from theoretical statistical mechanics. We showed how this class of Markov fields it can be built based on a statistical dependency structures inferred on information theoretical grounds over empirical data. Thus, aside from purely theoretical interest, the Tensor Markov Fields described here may be useful for mathematical modeling and data analysis due to their intrinsic simplicity and generality.
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BACKGROUND: Currently, thanks to the growing number of public database resources, most evidence on planning and management, healthcare institutions, policies and practices is becoming available to everyone. However, one of the limitations for the advancement of data and literature-driven research has been the lack of flexibility of the methodological resources used in qualitative research. There is a need to incorporate friendly, cheaper and faster tools for the systematic, unbiased analysis of large data corpora, in particular regarding the qualitative aspects of the information (often overlooked). METHODS: This article proposes a series of novel techniques, exemplified by the case of the role of Institutional Committees of Bioethics to (1) massively identify the documents relevant to a given issue, (2) extract the fundamental content, focusing on qualitative analysis, (3) synthesize the findings in the published literature, (4) categorize and visualize the evidence, and (5) analyse and report the results. RESULTS: A critical study of the institutional role of public health policies and practices in Institutional Committees of Bioethics was used as an example application of the method. Interactive strategies were helpful to define and conceptualise variables, propose research questions and refine research interpretation. These methods are additional aids to systematic reviews, pre-coding schemes and construction of a priori diagrams to survey and analyse social science literature. CONCLUSIONS: These novel methods have proven to facilitate the formulation and testing of hypotheses on the subjects to be studied. Such tools may allow important advances going from descriptive approaches to decision-making and even institutional assessment and policy redesign, by pragmatic reason of time and costs.
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Atención a la Salud , Política de Salud , Proyectos de Investigación , Investigación , Bioética , Análisis de Datos , Toma de Decisiones , Humanos , Difusión de la Información , Salud Pública , Investigación Cualitativa , Ciencias SocialesRESUMEN
Gene regulation may be studied from an information-theoretic perspective. Gene regulatory programs are representations of the complete regulatory phenomenon associated to each biological state. In diseases such as cancer, these programs exhibit major alterations, which have been associated with the spatial organization of the genome into chromosomes. In this work, we analyze intrachromosomal, or cis-, and interchromosomal, or trans-gene regulatory programs in order to assess the differences that arise in the context of breast cancer. We find that using information theoretic approaches, it is possible to differentiate cis-and trans-regulatory programs in terms of the changes that they exhibit in the breast cancer context, indicating that in breast cancer there is a loss of trans-regulation. Finally, we use these programs to reconstruct a possible spatial relationship between chromosomes.
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The study of the effects associated with the electrostatic properties of DNA is of fundamental importance to understand both its molecular properties at the single molecule level, like the rigidity of the chain, and its interaction with other charged bio-molecules, including other DNA molecules; such interactions are crucial to maintain the thermodynamic stability of the intra-cellular medium. In the present work, we combine the Poisson-Boltzmann mean-field theory with an irreversible thermodynamic approximation to analyze the effects of counterion accumulation inside DNA on both the denaturation profile of the chain and the equation of state of the suspension. To this end, we model the DNA molecule as a porous charged cylinder immersed in an aqueous solution. These thermo-electrostatic effects are explicitly studied in the particular case of some genes for which damage in their sequence is associated with diffuse large B-cell lymphoma.
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ADN/química , Modelos Químicos , Desnaturalización de Ácido Nucleico , Iones/química , Conformación de Ácido Nucleico , Presión , Electricidad Estática , SuspensionesRESUMEN
BACKGROUND: Thyroid cancer (TC) is the most common malignant cancer of the Endocrine System. Histologically, there are three main subtypes of TC: follicular, papillary and anaplastic. Diagnosing a thyroid tumor subtype with a high level of accuracy and confidence is still a difficult task because genetic, molecular and cellular mechanisms underlying the transition from differentiated to undifferentiated thyroid tumors are not well understood. A genome-wide analysis of these three subtypes of thyroid carcinoma was carried out in order to identify significant differences in expression levels as well as enriched pathways for non-shared molecular and cellular features between subtypes. RESULTS: Inhibition of matrix metalloproteinases pathway is a major event involved in thyroid cancer progression and its dysregulation may result crucial for invasiveness, migration and metastasis. This pathway is drastically altered in ATC while in FTC and PTC, the most important pathways are related to DNA-repair activation or cell to cell signaling events. CONCLUSION: A progression from FTC to PTC and then to ATC was detected and validated on two independent datasets. Moreover, PTX3, COLEC12 and PDGFRA genes were found as possible candidates for biomarkers of ATC while GPR110 could be tested to distinguish PTC over other tumor subtypes. The genome-wide analysis emphasizes the preponderance of pathway-dysregulation mechanisms over simple gene-malfunction as the main mechanism involved in the development of a cancer phenotype.
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Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Transducción de Señal , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Biomarcadores , Comunicación Celular , Supervivencia Celular/genética , Biología Computacional , Bases de Datos Genéticas , Humanos , Anotación de Secuencia Molecular , Clasificación del Tumor , Curva ROC , Reproducibilidad de los Resultados , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patologíaRESUMEN
BACKGROUND: In the present paper we will examine methodological frameworks to study complex genetic diseases (e.g. cancer) from the stand point of theoretical-computational biology combining both data-driven and hypothesis driven approaches. Our work focuses in the apparent counterpoint between two formal approaches to research in natural science: data- and hypothesis-driven inquiries. For a long time philosophers have recognized the mechanistic character of molecular biology explanations. On these grounds we suggest that hypothesis and data-driven approaches are not opposed to each other but that they may be integrated by the development of what we call enriched mechanistic models. METHODS: We will elaborate around a case study from our laboratory that analyzed the relationship between transcriptional de-regulation of sets of genes that present both transcription factor and metabolic activity while at the same time have been associated with the presence of cancer. The way we do this is by analyzing structural, mechanistic and functional approaches to molecular level research in cancer biology. Emphasis will be given to data integration strategies to construct new explanations. RESULTS: Such analysis has led us to present a mechanistic-enriched model of the phenomenon. Such model pointed out to the way in which regulatory and thermodynamical behavior of gene regulation networks may be analyzed by means of gene expression data obtained from genome-wide analysis experiments in RNA from biopsy-captured tissue. The foundations of the model are given by the laws of thermodynamics and chemical physics and the approach is an enriched version of a mechanistic explanation. CONCLUSION: After analyzing the way we studied the coupling of metabolic and transcriptional deregulation in breast cancer, we have concluded that one plausible strategy to integrate data driven and hypothesis driven approaches is by means of resorting to fundamental and well established laws of physics and chemistry since these provide a solid ground for assessment.
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Redes Reguladoras de Genes , Modelos Genéticos , Neoplasias/genética , Neoplasias/metabolismo , Factores de Transcripción/metabolismo , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Genómica , Humanos , Modelos MolecularesRESUMEN
To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase-mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease.
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Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Mutación , Secuencias de Aminoácidos , Análisis por Conglomerados , Análisis Mutacional de ADN , Exoma , Exones , Humanos , Modelos Genéticos , Reacción en Cadena de la Polimerasa/métodos , Análisis de Secuencia de ADN , Translocación GenéticaRESUMEN
Lung tumors are a leading cause of cancer-related death worldwide. Lung cancers are highly heterogeneous on their phenotypes, both at the cellular and molecular levels. Efforts to better understand the biological origins and outcomes of lung cancer in terms of this enormous variability often require of high-throughput experimental techniques paired with advanced data analytics. Anticipated advancements in multi-omic methodologies hold potential to reveal a broader molecular perspective of these tumors. This study introduces a theoretical and computational framework for generating network models depicting regulatory constraints on biological functions in a semi-automated way. The approach successfully identifies enriched functions in analyzed omics data, focusing on Adenocarcinoma (LUAD) and Squamous cell carcinoma (LUSC, a type of NSCLC) in the lung. Valuable information about novel regulatory characteristics, supported by robust biological reasoning, is illustrated, for instance by considering the role of genes, miRNAs and CpG sites associated with NSCLC, both novel and previously reported. Utilizing multi-omic regulatory networks, we constructed robust models elucidating omics data interconnectedness, enabling systematic generation of mechanistic hypotheses. These findings offer insights into complex regulatory mechanisms underlying these cancer types, paving the way for further exploring their molecular complexity.
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Breast cancer, characterized by its complexity and diversity, presents significant challenges in understanding its underlying biology. In this study, we employed gene co-expression network analysis to investigate the gene composition and functional patterns in breast cancer subtypes and normal breast tissue. Our objective was to elucidate the detailed immunological features distinguishing these tumors at the transcriptional level and to explore their implications for diagnosis and treatment. The analysis identified nine distinct gene module clusters, each representing unique transcriptional signatures within breast cancer subtypes and normal tissue. Interestingly, while some clusters exhibited high similarity in gene composition between normal tissue and certain subtypes, others showed lower similarity and shared traits. These clusters provided insights into the immune responses within breast cancer subtypes, revealing diverse immunological functions, including innate and adaptive immune responses. Our findings contribute to a deeper understanding of the molecular mechanisms underlying breast cancer subtypes and highlight their unique characteristics. The immunological signatures identified in this study hold potential implications for diagnostic and therapeutic strategies. Additionally, the network-based approach introduced herein presents a valuable framework for understanding the complexities of other diseases and elucidating their underlying biology.
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Neoplasias de la Mama , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Inflamación , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Femenino , Inflamación/inmunología , Inflamación/genética , Transcriptoma , Biomarcadores de Tumor/genéticaRESUMEN
Cardiovascular diseases stand as a prominent global cause of mortality, their intricate origins often entwined with comorbidities and multimorbid conditions. Acknowledging the pivotal roles of age, sex, and social determinants of health in shaping the onset and progression of these diseases, our study delves into the nuanced interplay between life-stage, socioeconomic status, and comorbidity patterns within cardiovascular diseases. Leveraging data from a cross-sectional survey encompassing Mexican adults, we unearth a robust association between these variables and the prevalence of comorbidities linked to cardiovascular conditions. To foster a comprehensive understanding of multimorbidity patterns across diverse life-stages, we scrutinize an extensive dataset comprising 47,377 cases diagnosed with cardiovascular ailments at Mexico's national reference hospital. Extracting sociodemographic details, primary diagnoses prompting hospitalization, and additional conditions identified through ICD-10 codes, we unveil subtle yet significant associations and discuss pertinent specific cases. Our results underscore a noteworthy trend: younger patients of lower socioeconomic status exhibit a heightened likelihood of cardiovascular comorbidities compared to their older counterparts with a higher socioeconomic status. By empowering clinicians to discern non-evident comorbidities, our study aims to refine therapeutic designs. These findings offer profound insights into the intricate interplay among life-stage, socioeconomic status, and comorbidity patterns within cardiovascular diseases. Armed with data-supported approaches that account for these factors, clinical practices stand to be enhanced, and public health policies informed, ultimately advancing the prevention and management of cardiovascular disease in Mexico.
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This study investigated the relationship between Metabolic Syndrome (MetS), sleep disorders, the consumption of some nutrients, and social development factors, focusing on gender differences in an unbalanced dataset from a Mexico City cohort. We used data balancing techniques like SMOTE and ADASYN after employing machine learning models like random forest and RPART to predict MetS. Random forest excelled, achieving significant, balanced accuracy, indicating its robustness in predicting MetS and achieving a balanced accuracy of approximately 87%. Key predictors for men included body mass index and family history of gout, while waist circumference and glucose levels were most significant for women. In relation to diet, sleep quality, and social development, metabolic syndrome in men was associated with high lactose and carbohydrate intake, educational lag, living with a partner without marrying, and lack of durable goods, whereas in women, best predictors in these dimensions include protein, fructose, and cholesterol intake, copper metabolites, snoring, sobbing, drowsiness, sanitary adequacy, and anxiety. These findings underscore the need for personalized approaches in managing MetS and point to a promising direction for future research into the interplay between social factors, sleep disorders, and metabolic health, which mainly depend on nutrient consumption by region.
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Síndrome Metabólico , Trastornos del Sueño-Vigilia , Masculino , Humanos , Femenino , Síndrome Metabólico/complicaciones , Calidad del Sueño , Cambio Social , Ingestión de Alimentos , Circunferencia de la Cintura , Índice de Masa Corporal , Trastornos del Sueño-Vigilia/complicaciones , Aprendizaje Automático , Factores de RiesgoRESUMEN
It has been documented that variations in glycosylation on glycoprotein hormones, confer distinctly different biological features to the corresponding glycoforms when multiple in vitro biochemical readings are analyzed. We here applied next generation RNA sequencing to explore changes in the transcriptome of rat granulosa cells exposed for 0, 6, and 12 h to 100 ng/ml of four highly purified follicle-stimulating hormone (FSH) glycoforms, each exhibiting different glycosylation patterns: a. human pituitary FSH18/21 (hypo-glycosylated); b. human pituitary FSH24 (fully glycosylated); c. Equine FSH (eqFSH) (hypo-glycosylated); and d. Chinese-hamster ovary cell-derived human recombinant FSH (recFSH) (fully-glycosylated). Total RNA from triplicate incubations was prepared from FSH glycoform-exposed cultured granulosa cells obtained from DES-pretreated immature female rats, and RNA libraries were sequenced in a HighSeq 2500 sequencer (2 x 125 bp paired-end format, 10-15 x 106 reads/sample). The computational workflow focused on investigating differences among the four FSH glycoforms at three levels: gene expression, enriched biological processes, and perturbed pathways. Among the top 200 differentially expressed genes, only 4 (0.6%) were shared by all 4 glycoforms at 6 h, whereas 118 genes (40%) were shared at 12 h. Follicle-stimulating hormone glycocoforms stimulated different patterns of exclusive and associated up regulated biological processes in a glycoform and time-dependent fashion with more shared biological processes after 12 h of exposure and fewer treatment-specific ones, except for recFSH, which exhibited stronger responses with more specifically associated processes at this time. Similar results were found for down-regulated processes, with a greater number of processes at 6 h or 12 h, depending on the particular glycoform. In general, there were fewer downregulated than upregulated processes at both 6 h and 12 h, with FSH18/21 exhibiting the largest number of down-regulated associated processes at 6 h while eqFSH exhibited the greatest number at 12 h. Signaling cascades, largely linked to cAMP-PKA, MAPK, and PI3/AKT pathways were detected as differentially activated by the glycoforms, with each glycoform exhibiting its own molecular signature. These data extend previous observations demonstrating glycosylation-dependent distinctly different regulation of gene expression and intracellular signaling pathways triggered by FSH in granulosa cells. The results also suggest the importance of individual FSH glycoform glycosylation for the conformation of the ligand-receptor complex and induced signalling pathways.
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Hormona Folículo Estimulante , Células de la Granulosa , Transcriptoma , Animales , Femenino , Células de la Granulosa/metabolismo , Células de la Granulosa/efectos de los fármacos , Hormona Folículo Estimulante/farmacología , Hormona Folículo Estimulante/metabolismo , Ratas , Glicosilación , Transcriptoma/efectos de los fármacos , Humanos , Células Cultivadas , RNA-Seq/métodos , Células CHO , CricetulusRESUMEN
Breast cancer is a complex disease that is influenced by the concurrent influence of multiple genetic and environmental factors. Recent advances in genomics and other high throughput biomolecular techniques (-omics) have provided numerous insights into the molecular mechanisms underlying breast cancer development and progression. A number of these mechanisms involve multiple layers of regulation. In this review, we summarize the current knowledge on the role of multiple omics in the regulation of breast cancer, including the effects of DNA methylation, non-coding RNA, and other epigenomic changes. We comment on how integrating such diverse mechanisms is envisioned as key to a more comprehensive understanding of breast carcinogenesis and cancer biology with relevance to prognostics, diagnostics and therapeutics. We also discuss the potential clinical implications of these findings and highlight areas for future research. Overall, our understanding of the molecular mechanisms of multi-omic regulation in breast cancer is rapidly increasing and has the potential to inform the development of novel therapeutic approaches for this disease.
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Neuroblastoma represents a neoplastic expansion of neural crest cells in the developing sympathetic nervous system and is childhood's most common extracranial solid tumor. The heterogeneity of gene expression in different types of cancer is well-documented, and genetic features of neuroblastoma have been described by classification, development stage, malignancy, and progression of tumors. Here, we aim to analyze RNA sequencing datasets, publicly available in the GDC data portal, of neuroblastoma tumor samples from various patients and compare them with normal adrenal gland tissue from the GTEx data portal to elucidate the gene expression profile and regulation networks they share. Our results from the differential expression, weighted correlation network, and functional enrichment analyses that we performed with the count data from neuroblastoma and standard normal gland samples indicate that the analysis of transcriptome data from 58 patients diagnosed with high-risk neuroblastoma shares the expression pattern of 104 genes. More importantly, our analyses identify the co-expression relationship and the role of these genes in multiple biological processes and signaling pathways strongly associated with this disease phenotype. Our approach proposes a group of genes and their biological functions to be further investigated as essential molecules and possible therapeutic targets of neuroblastoma regardless of the etiology of individual tumors.