Biology subjects

Garcia-Garcia, F.

Publications and source records attributed to Garcia-Garcia, F..

27 records · Page 2Linked to original sources

bioRxiv2023

Lipid network of plasma extracellular vesicles reveals sex-based differences in the lipidomic profile from patients with alcohol use disorder

Alcohol use disorder (AUD) is one of the most common psychiatric disorders, and the consumption of this substance is considered one of the main causes of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes, however little is known about the role of lipids containing extracellular vesicles (EVs), as regulatory molecules and biomarkers. In this study, a highly sensitive lipidomic strategy is employed to characterize plasma EV lipid species from individuals with AUD, to evaluate differential functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism in the alcohol consumption. Plasma EV lipids from female and male patients with AUD and healthy individuals were analyzed to obtain lipid differential abundance, as well as biological interpretation of LINEX2 lipidomics data, evaluating enzymatic dysregulation through an enrichment algorithm. Our results showed for the first time that females with AUD exhibit greater substrate-product changes in LPC and PC lipids, as well as phospholipases and acyltransferases activity, potentially linked to cancer progression and neuroinflammation. Conversely, males with AUD showed dysregulation in Cer and SM lipid, involving sphingomyelinases, sphingomyelin phosphodiesterase, and sphingomyelin synthase, which could be related with hepatotoxicity. Notably, females with AUD showed LION-terms associated with "positive intrinsic curvature", while males exhibited "negative intrinsic curvature, contributing to vesicle fusion processes. These methodological developments allow a better understanding of lipid metabolism and its regulatory mechanisms, which contributes not only to identify novel lipid targets, but also the discovery of sex-specific clinical biomarkers in the AUD.

pathology↗

bioRxiv2023

An integrated approach to identify sex-specific genes, transcription factors, and pathways in Alzheimer's disease

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/556293v3_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@4a60d7org.highwire.dtl.DTLVardef@11bd7eborg.highwire.dtl.DTLVardef@fc9b69org.highwire.dtl.DTLVardef@3f239f_HPS_FORMAT_FIGEXP M_FIG C_FIG BackgroundAge represents a significant risk factor for the development of Alzheimers disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions. MethodsThe exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity. ResultsWe selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, A{beta} aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD (https://bioinfo.cipf.es/metafun-ad/). ConclusionOur meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. These sex-based differences will represent the basis for new hypotheses and could significantly impact precision medicine and improve diagnosis and clinical outcomes in AD patients. HighlightsO_LIFemale AD patients possess more affected genes than male AD patients. C_LIO_LI389 genes from the sex-based differential impact on disease comparison significantly impact the cerebral cortex and suggest a more significant effect on cognitive function in female AD patients. C_LIO_LIThe cluster of repressed genes in female AD patients functionally impacts glutamate and GABA neurotransmitters and A{beta} deposition. C_LIO_LIFemale AD patients exhibit several transcription factors with significantly different activity patterns compared to male AD patients. C_LIO_LIThis work includes Metafun-AD, an open and interactive web tool to explore all generated data and results. C_LI

neuroscience↗

bioRxiv2023

The role of microRNAs to understand sex-based differences in Alzheimer's disease

BackgroundThe incidence of Alzheimers disease (AD) - the most frequent cause of dementia - is expected to increase as life expectancies rise across the globe. While sex-based differences in AD have previously been described, there remain uncertainties regarding any association between sex and disease-associated molecular mechanisms. Studying sex-specific expression profiles of regulatory factors such as microRNAs (miRNAs) could contribute to more accurate disease diagnosis and treatment. MethodsA systematic review identified five studies of microRNA expression in AD patients that incorporated information regarding the biological sex of samples in the Gene Expression Omnibus repository. A differential microRNA expression analysis was performed, considering disease status and patient sex. Subsequently, results were integrated within a meta-analysis methodology, with a functional enrichment of meta-analysis results establishing an association between altered miRNA expression and relevant Gene Ontology terms. ResultsMeta-analyses of miRNA expression profiles in blood samples revealed the alteration of sixteen miRNAs in female and twenty-two miRNAs in male AD patients. We discovered nine miRNAs commonly overexpressed in both sexes, suggesting a shared miRNA dysregulation profile. Functional enrichment results based on miRNA profiles revealed sex-based differences in biological processes; most affected processes related to ubiquitination, regulation of different kinase activities, and apoptotic processes in males, but RNA splicing and translation in females. Meta-analyses of miRNA expression profiles in brain samples revealed the alteration of six miRNAs in female and four miRNAs in male AD patients. We observed a single underexpressed miRNA in female and male AD patients (hsa-miR-767-5p); however, the functional enrichment analysis for brain samples did not reveal any specifically affected biological process. ConclusionsSex-specific meta-analyses supported the detection of differentially expressed miRNAs in female and male AD patients, highlighting the relevance of sex-based information in biomedical data. Further studies on miRNA regulation in AD patients should meet the criteria for comparability and standardization of information. HighlightsO_LIDeregulation of miRNA expression profiles occurs in a tissue- and sex-specific manner in AD patients C_LIO_LIMeta-analysis of blood samples revealed a partial overlapping pattern of altered miRNA expression in female and male AD patients C_LIO_LIFunctional enrichment based on AD-associated miRNA expression profiles in blood samples reveals sex-based differences: RNA splicing and translation in female AD patients and ubiquitination, regulation of different kinase activities, and apoptotic process in male AD patients C_LIO_LILinks between AD development and miRNA expression in brain tissue also demonstrate the influence of sex C_LI Plain English SummaryAlzheimers disease (AD) - a neurodegenerative disease mainly affecting older patients - is characterized by cognitive deterioration, memory loss, and progressive incapacitation in daily activities. While AD affects almost twice as many females as males, and cognitive deterioration and brain atrophy develop more rapidly in females, the biological causes of these differences remain poorly understood. MicroRNAs (miRNAs) regulate gene expression and impact a wide variety of biological processes; therefore, studying the differential expression of miRNAs in female and male AD patients could contribute to a better understanding of the disease. We reviewed studies of miRNA expression in female and male AD patients and integrated results using a meta-analysis methodology and then identified those genes regulated by the altered miRNAs to establish an association with biological processes. We found sixteen (females) and twenty-two (males) miRNAs altered in the blood of AD patients. Functional enrichment revealed sex-based differences in the affected altered biological processes - protein modification and degradation and cell death in male AD patients and RNA processing in female AD patients. A similar analysis in the brains of AD patients revealed six (females) and four (males) miRNAs with altered expression; however, our analysis failed to highlight any specifically altered biological processes. Overall, we highlight the sex-based differential expression of miRNAs (and biological processes affected) in the blood and brain of AD patients.

neuroscience↗

bioRxiv2023

A comprehensive transcriptional signature in pancreatic ductal adenocarcinoma reveals new insights into the immune and desmoplastic microenvironment

Pancreatic ductal adenocarcinoma (PDAC) prognosis and treatment response remains devastatingly poor due partly to the highly heterogeneous, aggressive, and immunosuppressive nature of this tumor type. The intricate relationship between stroma, inflammation, and immunity remains vaguely understood in the PDAC microenvironment. Here, we performed a meta-analysis of stroma-, and immune-related gene expression in the PDAC microenvironment to improve disease prognosis and therapeutic development. We selected twenty-one PDAC studies from the Gene Expression Omnibus and ArrayExpress databases, including 922 samples (320 controls and 602 cases). Differential gene enrichment analysis identified 1153 significant dysregulated genes in PDAC patients that contribute to a desmoplastic stroma and an immunosuppressive environment (the hallmarks of PDAC tumors). The results highlighted two gene signatures related to the immune and stromal environments that cluster PDAC patients in high- and low-risk groups, impacting patient stratification and therapeutic decision-making. Moreover, HCP5, SLFN13, IRF9, IFIT2, and IFI35 immune genes were related to prognosis value in PDAC patients, for the first time. Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with few curative options. Desmoplastic stroma and immune system evasion in PDAC represent challenges to the success of therapeutic strategies that function well in other tumor types. Characterizing the PDAC microenvironment (including the immune environment) remains critical to developing safe and efficient therapies. Here, we present a comprehensive meta-analysis identifying 1153 significantly dysregulated genes, which mainly impact extracellular matrix remodeling and the immune system. We identify two signatures of twenty-eight immune-related genes and eleven stroma-related genes influencing PDAC patient survival. Additionally, five immune genes are associated with PDAC prognosis for the first time.

cancer biology↗

bioRxiv2023

Systematic review and meta-analysis of transcriptomic studies on different brain regions reveals different sex-based profiles in schizophrenic patients

BackgroundSchizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society despite its relatively low prevalence. Previous studies have suggested that the dopamine D2 receptor gene and genes involved in glutamatergic neurotransmission, synaptic plasticity, and immune function as genetic risk factors. Sex-based differences also exist in schizophrenia epidemiology, symptomatology and outcomes; however, we lack a transcriptomic profile that considers sex and differentiates specific cerebral regions. MethodsWe performed a systematic review on bulk RNA-sequencing studies of post-mortem brain samples. Then, we fulfilled differential expression analysis on each study and summarized their results with regions-specific meta-analyses (prefrontal cortex and hippocampus) and a global all-studies meta-analysis. Finally, we used the consensus transcriptomic profiles to functionally characterize the impact of schizophrenia in males and females by protein-protein interaction networks, enriched biological processes and dysregulated transcription factors. ResultsWe discovered the sex-based dysregulation of 265 genes in the prefrontal, 1.414 genes in the hippocampus and 66 genes in the all-studies meta-analyses. The functional characterization of these gene sets unveiled increased processes related to immune response functions in the prefrontal cortex in male and the hippocampus in female schizophrenia patients and the overexpression of genes related to neurotransmission and synapses in the prefrontal cortex of female schizophrenia patients. Considering a meta-analysis of all brain regions available, we encountered the relative overexpression of genes related to synaptic plasticity and transmission in female and the overexpression of genes involved in organizing genetic information and protein folding in male schizophrenia patients. The protein-protein interaction networks and transcription factors activity analyses supported these sex-based profiles. ConclusionsOur results report multiple sex-based transcriptomic alterations in specific brain regions of schizophrenia patients, which provides new insight into the role of sex in schizophrenia. Moreover, we unveil a partial overlapping of inflammatory processes in the prefrontal cortex of males and the hippocampus of females. Plain language summarySchizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society. Previous studies have suggested dopamine and glutamate neurotransmission genes, as well as immune function alteration as genetic risk factors. Schizophrenia epidemiology, symptomatology and outcomes are different for women and men, but the biological reason is not understood. Therefore, we reviewed all RNA-sequencing studies of post-mortem brain samples of women and men affected by schizophrenia available. Then, we compared the gene expression on each study for males and females and integrated the results of studies on different regions meta-analyses: prefrontal cortex, hippocampus and all-studies. Finally, we functionally characterize the impact of schizophrenia in males and females by protein-protein interaction networks, enriched biological processes and dysregulated transcription factors. We discovered the sex-based dysregulation of 265 genes in the prefrontal cortex, 1.414 genes in the hippocampus and 66 genes in the all-studies meta-analyses. The functional characterization of these genes unveiled increased immune response functions in the prefrontal cortex in men and the hippocampus in women schizophrenia patients, as well as increased neurotransmission and synapses in the prefrontal cortex of female schizophrenia patients. The protein-protein interaction networks and transcription factors activity analyses supported these sex-based profiles. Our results report multiple transcriptomic alterations in specific brain regions of schizophrenia patients, which provides new insight into the role of sex in schizophrenia. Moreover, we unveil a partial overlapping of inflammatory processes in the prefrontal cortex of males and the hippocampus of females. HighlightsO_LIThe expression of 265 genes is altered in the prefrontal cortex of schizophrenic patients, being overexpressed in females those related to synaptic transmission. C_LIO_LIIn the prefrontal cortex of males, overexpressed genes and overactivated transcription factors are linked to immune response and inflammation. C_LIO_LIConversely, genes and transcription factors more activated in the hippocampus of females are related to immune response, whereas those genes more expressed in males are linked to protein processing. C_LIO_LIThe global meta-analysis unveils groups of long non-coding genes and pseudogenes differentially expressed in males and females. C_LIO_LIThe effects of schizophrenia are closely related in the prefrontal cortex of males and the hippocampus of females. C_LI

molecular biology↗

bioRxiv2022

DNA Methylation Signatures in Breast Cancer: A Systematic Review and Meta-Analysis

Epigenetic changes are involved in the onset and progression of cancer, and the detection of DNA methylation signatures may foster the improvement of diagnosis and prognosis. While the emergence of innovative technologies has fostered numerous studies in breast cancer, many lack statistical power due to the small sample sizes generally involved. In this study, we present a novel meta-analysis that identifies a common pattern of DNA methylation in all breast cancer subtypes. We obtained DNA methylation signatures at the gene and biological function level, identifying those significant groups of genes and functional pathways affected. To achieve this, we conducted a thorough systematic review following PRISMA statement guidelines for the selection of studies on DNA methylation in breast cancer. In total, we gathered four studies (GSE52865, GSE141338, GSE59901 and GSE101443) that were split into 13 comparisons comprising a set of 144 individuals. We discovered that most breast cancer subtypes share a significant deregulation in the immune system and alterations to the cell cycle. This integrative approach combines all available information from public data repositories and possesses greater statistical power than any individual study. Further evaluations of the identified differential biological processes and pathways may support the identification of novel biomarkers and therapeutic targets. Simple summaryThe identification of DNA methylation patterns in breast cancer represents a potentially valuable approach in defining more accurate diagnoses and treatment options. In this study, we applied a novel methodology that integrates the DNA methylation profiles of all studies available in public repositories via systematic review and meta-analysis. The results provide evidence of a common DNA methylation signature in distinct breast cancer subtypes, which reflects a significant deregulation of the immune system and alterations to the cell cycle. Overall, these results may support the selection of disease/treatment biomarkers and the identification of therapeutic targets.

cancer biology↗

bioRxiv2021

Sex bias evaluation of classic and novel Housekeeping Genes in adipose tissue through the massive analysis of transcriptomics data

BackgroundAs the housekeeping genes (HKG) generally involved in maintaining essential cell functions are typically assumed to exhibit constant expression levels across cell types, they are commonly employed as internal controls in gene expression studies. Nevertheless, HKG may vary gene expression profile according to different variables introducing systematic errors into experimental results. Sex bias can indeed affect expression display, however, up to date, sex has not been typically considered as a biological variable. MethodsIn this study, we evaluate the expression profiles of six classical housekeeping genes (four metabolic: GAPDH, HPRT, PPIA, and UBC, and two ribosomal: 18S and RPL19) to determine expression stability in adipose tissues (AT) of Homo sapiens and Mus musculus and check sex bias and their overall suitability as internal controls. We also assess the expression stability of all genes included in distinct whole-transcriptome microarrays available from the Gene Expression Omnibus database to identify sex-unbiased housekeeping genes (suHKG) suitable for use as internal controls. We perform a novel computational strategy based on meta-analysis techniques to identify any sexual dimorphisms in mRNA expression stability in AT and to properly validate potential candidates. ResultsJust above half of the considered studies informed properly about the sex of the human samples, however, not enough female mouse samples were found to be included in this analysis. We found differences in the HKG expression stability in humans between female and male samples, with females presenting greater instability. We propose a suHKG signature including experimentally validated classical HKG like PPIA and RPL19 and novel potential markers for human AT and discarding others like the extensively used 18S gene due to a sex-based variability display in adipose tissue. Orthologs have also been assayed and proposed for mouse WAT suHKG signature. All results generated during this study are readily available by accessing an open web resource (https://bioinfo.cipf.es/metafun-HKG) for consultation and reuse in further studies. ConclusionsThis sex-based research proves that certain classical housekeeping genes fail to function adequately as controls when analyzing human adipose tissue considering sex as a variable. We confirm RPL19 and PPIA suitability as sex-unbiased human and mouse housekeeping genes derived from sex-specific expression profiles, and propose new ones such as RPS8 and UBB. HighlightsO_LIA computational strategy based on massive data analysis revealed that an accurate experimental design for adipose tissue requires the adequate selection of a sex-unbiased housekeeping genes (HKG). C_LIO_LIThe extensively used 18S gene displays sex-based variability in adipose tissue, although PPIA and RPL19 do not, and hence, represent robust HKG. C_LIO_LINew sex-unbiased human and mouse candidate HKG: RPS8 and UBB. C_LIO_LImetafun-HKG (https://bioinfo.cipf.es/metafun-HKG): a freely available web tool to allow users to review stable expression levels of candidate HKG along the large volume of FAIR data. C_LI

genomics↗

bioRxiv2021

MetaFun: Unveiling sex differences in multiple omics studies through comprehensive functional meta-analysis

While sex-based differences in various health scenarios have been thoroughly acknowledged in the literature, we lack a deep analysis of sex as a variable in this context. To fill this knowledge gap, we created MetaFun as an easy-to-use web-based tool to meta-analyze multiple transcriptomic datasets with a sex-based perspective to gain major statistical power and biological soundness. Furthermore, MetaFun can be used to perform case-control meta-analyses, allowing researchers with basic programming skills to access this methodology. Availability and implementationMetaFun is freely available at http://bioinfo.cipf.es/metafun The back end was implemented in R and Java, and the front end was developed using Angular Contactfgarcia@cipf.es, mhidalgo@cipf.es Supplementary informationR code available at https://gitlab.com/ubb-cipf/metafunr

bioinformatics↗

bioRxiv2020

Unveiling sex-based differences in the effects of alcohol abuse: a comprehensive functional meta-analysis of transcriptomic studies

The abuse of alcohol, one of the most popular psychoactive substances, can cause several pathological and psychological consequences, including alcohol use disorder (AUD). An impaired ability to stop or control alcohol intake despite adverse health or social consequences characterize AUD. While AUDs predominantly occur in men, growing evidence suggests the existence of distinct cognitive and biological consequences of alcohol dependence in women. The molecular and physiological mechanisms participating in these differential effects remain unknown. Transcriptomic technology permits the detection of the biological mechanisms responsible for such sex-based differences, which supports the subsequent development of novel personalized therapeutics to treat AUD. We conducted a systematic review and meta-analysis of transcriptomics studies regarding alcohol dependence in humans with representation from both sexes. For each study, we processed and analyzed transcriptomic data to obtain a functional profile of pathways and biological functions and then integrated the resulting data by meta-analysis to characterize any sex-based transcriptomic differences associated with AUD. Global results of the transcriptomic analysis revealed the association of decreased tissue regeneration, embryo malformations, altered intracellular transport, and increased rate of RNA and protein replacement with female AUD patients. Meanwhile, our analysis indicated that increased inflammatory response and blood pressure and a reduction in DNA repair capabilities associated with male AUD patients. In summary, our functional meta-analysis of transcriptomic studies provides evidence for differential biological mechanisms that AUD patients of differing sex. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/254185v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@13c9becorg.highwire.dtl.DTLVardef@20aac4org.highwire.dtl.DTLVardef@ab5502org.highwire.dtl.DTLVardef@5a0d37_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗