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The human microbiome is a complex ecosystem that plays a crucial role in maintaining human health and well-being. The gut microbiome, in particular, has been extensively studied due to its critical functions in nutrient extraction, immune system regulation, and mental health. However, the vast variability in the composition of microbial communities across individuals and populations poses a challenge in microbiome research and is an obstacle for the development of interventions. Reference microbiome data sets and standardized pipelines for the analysis of microbiome data have been developed to overcome this challenge, however, they are largely static and cannot be improved with user-generated data. Here, we introduce an application programming interface (API) that allows for the dynamic estimation of reference intervals for gut microbiota functional abundances using the refineR algorithm. Importantly, our API can continuously adapt to changes in gut microbiota profiles stored in a local database and allows the improvement of existing reference data for a given condition over time by the incorporation of new data from different individuals or populations. We demonstrate the usefulness of our API by generating a basal gut microbiota profile of a healthy Turkish population and estimating reference intervals for the functional abundance of manually selected Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Our study highlights the potential of APIs in facilitating microbiome research by providing a dynamic and customizable tool for estimating reference intervals for gut microbiota functional abundances. [ABSTRACT FROM AUTHOR]

Transposable elements (TEs) have been implicated in autism spectrum disorder (ASD). However, our understanding of their roles is far from complete. Herein, we explored de novo TE insertions (dnTEIs) and de novo variants (DNVs) across the genomes of dizygotic twins with ASD and their parents. The neuronal regulatory elements had a tendency to harbor dnTEIs that were shared between twins, but ASD-risk genes had dnTEIs that were unique to each twin. The dnTEIs were 4.6-fold enriched in enhancers that are active in embryonic stem cell (ESC)-neurons (p < 0.001), but DNVs were 1.5-fold enriched in active enhancers of astrocytes (p = 0.0051). Our findings suggest that dnTEIs and DNVs play a role in ASD etiology by disrupting enhancers of neurons and astrocytes. [ABSTRACT FROM AUTHOR]

Bladder cancer is mostly present in the form of urothelium carcinoma, causing over 150,000 deaths each year. Its histopathological classification as muscle invasive (MIBC) and non-muscle invasive (NMIBC) is the most prominent aspect, affecting the prognosis and progression of this disease. In this study, we defined the active regulatory landscape of MIBC and NMIBC cell lines using H3K27ac ChIP-seq and used an integrative approach to combine our findings with existing data. Our analysis revealed FRA1 and FLI1 as two critical transcription factors differentially regulating MIBC regulatory landscape. We show that FRA1 and FLI1 regulate the genes involved in epithelial cell migration and cell junction organization. Knock-down of FRA1 and FLI1 in MIBC revealed the downregulation of several EMT-related genes such as MAP4K4 and FLOT1. Further, ChIP-SICAP performed for FRA1 and FLI1 enabled us to infer chromatin binding partners of these transcription factors and link this information with their target genes. Finally, we show that knock-down of FRA1 and FLI1 result in significant reduction of invasion capacity of MIBC cells towards muscle microenvironment using IC-CHIP assays. Our results collectively highlight the role of these transcription factors in selection and design of targeted options for treatment of MIBC. The transcription factors FRA1 and FLI1 regulate cell migration and cell junction organization genes in muscle-invasive bladder cancer, and loss of these factors reduces cancer cell invasion, pointing toward a therapeutic avenue. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most severe neurodegenerative diseases observed in the elderly population. Although the hallmarks of AD have been identified, the methods for its definitive diagnosis and treatment are still lacking. Extracellular vesicles (EVs) have become a promising source for biomarkers since the identification of their content. EVs are released from multiple cell types and, when released from neurons, they pass from the brain to the blood with their cargo molecules. Hence, neuron-specific EV-resident microRNAs (miRNAs) are promising biomarkers for diagnosis of AD. This study aimed to identify altered miRNA content in small neuron-derived extracellular vesicles (sNDEVs) isolated from AD patients and healthy individuals. Furthermore, we examined the role of sNDEV-resident miRNAs in neuron-glia cellular interaction to understand their role in AD propagation. We identified 10 differentially expressed miRNAs in the sNDEVs of patients via next-generation sequencing and validated the most dysregulated miRNA, let-7e, with qRT-PCR. Let-7e was significantly increased in the sNDEVs of AD patients compared with those of healthy controls in a larger cohort. First, we evaluated the diagnostic utility of let-7e via ROC curve analysis, which revealed an AUC value of 0.9214. We found that IL-6 gene expression was increased in human microglia after treatment with sNDEVs of AD patients with a high amount of let-7e. Our study suggests that sNDEV-resident let-7e is a potential biomarker for AD diagnosis, and that AD patient-derived sNDEVs induce a neuroinflammatory response in microglia. [ABSTRACT FROM AUTHOR]

Purpose: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with lack of effective systemic chemotherapy. In this study, we aimed to evaluate the value of ATPase family AAA domain-containing protein 2 (ATAD2) as a biomarker and potential therapeutic target for HCC. Methods: The expression of ATAD2 was tested in different HCC patient cohorts by immunohistochemistry and comparative transcriptional analysis. The co-expression of ATAD2 and proliferation markers was compared during liver regeneration and malignancy with different bioinformatics tools. The cellular effects of ATAD2 inactivation in liver malignancy was tested on cell cycle, apoptosis, and colony formation ability as well as tumor formation using RNA interference. The genes affected by ATAD2 inactivation in three different HCC cell lines were identified by global gene expression profiling and bioinformatics tools. Results: ATAD2 overexpression is closely correlated with HCC tumor stage. There was gradual increase from dysplasia, well-differentiated and poorly-differentiated HCC, respectively. We also observed transient upregulation of ATAD2 expression during rat liver regeneration in parallel to changes in Ki-67 expression. ATAD2 knockdown resulted in apoptosis and decreased cell survival in vitro and decreased tumor formation in some HCC cell lines. However, three other HCC cell lines tested were not affected. Similarly, gene expression response to ATAD2 inactivation in different HCC cell lines was highly heterogeneous. Conclusions: ATAD2 is a potential proliferation marker for liver regeneration and HCC. It may also serve as a therapeutic target despite heterogeneous response of malignant cells. [ABSTRACT FROM AUTHOR]

Urothelial carcinoma of the bladder is the most frequent bladder cancer affecting more than 400,000 people each year. Histopathologically, it is mainly characterized as muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). Recently, the studies largely driven by consortiums such as TCGA identified the mutational landscape of both MIBC and NMIBC and determined the molecular subtypes of bladder cancer. Because of the exceptionally high rate of mutations in chromatin proteins, bladder cancer is thought to be a disease of chromatin, pointing out to the importance of studying epigenetic deregulation and the regulatory landscape of this cancer. In this study, we have analyzed ATAC-seq data generated for MIBC and integrated our findings with gene expression and DNA methylation data to identify subgroup specific regulatory patterns for MIBC. Our computational analysis revealed three MIBC regulatory clusters, which we named as neuronal, non-neuronal and luminal outlier. We have identified target genes of neuronal regulatory elements to be involved in WNT signaling, while target genes of non-neuronal and luminal outlier regulatory regions were enriched in epithelial differentiation and drug metabolism, respectively. Neuronal regulatory elements were determined to be ß-catenin targets (p value = 3.59e−08) consisting of genes involved in neurogenesis such as FGF9, and PROX1, and significantly enriched for TCF/LEF binding sites (p value = 1e−584). Our results showed upregulation of ß-catenin targets regulated by neuronal regulatory elements in three different cohorts, implicating ß-catenin signature in neuronal bladder cancer. Further, integration with mutation data revealed significantly higher oncogenic exon 3 ß-catenin mutations in neuronal bladder cancer compared to non-neuronal (odds ratio = 31.33, p value = 1.786e−05). Our results for the first time identify regulatory elements characterizing neuronal bladder cancer and links these neuronal regulatory elements with WNT signaling via mutations in β-catenin and its destruction complex components. [ABSTRACT FROM AUTHOR]

Neurotransmitters and peptide hormones are secreted into outside the cell by a vesicle fusion process. Although non-coding RNA (ncRNA) that include microRNA (miRNA) regulates gene expression inside the cell where they are transcribed, extracellular miRNA has been recently discovered outside the cells, proposing that miRNA might be released to participate in cell-to-cell communication. Despite its importance of extracellular miRNA, the molecular mechanisms by which miRNA can be stored in vesicles and released by vesicle fusion remain enigmatic. Using next-generation sequencing, vesicle purification techniques, and synthetic neurotransmission, we observe that large dense-core vesicles (LDCVs) contain a variety of miRNAs including miR-375. Furthermore, miRNA exocytosis is mediated by the SNARE complex and accelerated by Ca2+. Our results suggest that miRNA can be a novel neuromodulator that can be stored in vesicles and released by vesicle fusion together with classical neurotransmitters. [ABSTRACT FROM AUTHOR]