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Parkinson's disease (PD) is the second-most common neurodegenerative disease, and its pathophysiology is associated with alpha-synuclein accumulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. MicroRNAs are small non-coding RNAs that regulate gene expression, and many previous studies have described their dysregulation in plasma, CSF, and in the brain of patients with PD. In this study, we aimed to provide a regulatory network analysis on differentially expressed miRNAs in the brain of patients with PD. Based on our systematic review with a focus on the substantia nigra and the putamen, we found 99 differentially expressed miRNAs in brain samples from patients with PD, which regulate 135 target genes. Five genes associated with neuronal survival (BCL2, CCND1, FOXO3, MYC, and SIRT1) were modulated by dysregulated miRNAs found in the substantia nigra and the putamen of patients with PD. The functional enrichment analysis found FoxO and PI3K-AKT signaling as pathways related to PD. In conclusion, our comprehensive analysis of brain-related miRNA-mRNA regulatory networks in PD showed that mechanisms involving neuronal survival signaling, such as cell cycle control and regulation of autophagy/apoptosis, may be crucial for the neurodegeneration of PD, being a promising way for novel disease-modifying therapies.

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The role of regulatory elements such as small ncRNAs and their mechanisms are poorly understood in infectious diseases. Tuberculosis is one of the oldest infectious diseases of humans and it is still a challenge to prevent and treat. Control of the infection, as well as its diagnosis, are still complex and current treatments used are linked to several side effects. This study aimed to identify possible biomarkers for tuberculosis by applying NGS techniques to obtain global miRNA expression profiles from 22 blood samples of infected patients with tuberculosis (n = 9), their respective healthy physicians (n = 6) and external healthy individuals as controls (n = 7). Samples were run through a pipeline consisting of differential expression, target genes, gene set enrichment and miRNA-gene network analyses. We observed 153 altered miRNAs, among which only three DEmiRNAs (hsa-let-7g-5p, hsa-miR-486-3p and hsa-miR-4732-5p) were found between the investigated patients and their respective physicians. These DEmiRNAs are suggested to play an important role in granuloma regulation and their immune physiopathology. Our results indicate that miRNAs may be involved in immune modulation by regulating gene expression in cells of the immune system. Our findings encourage the application of miRNAs as potential biomarkers for tuberculosis.

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BACKGROUND: Next generation sequencing (NGS) has been a handy tool in clinical practice, mainly due to its efficiency and cost-effectiveness. It has been widely used in genetic diagnosis of several inherited diseases, and, in clinical oncology, it may enhance the discovery of new susceptibility genes and enable individualized care of cancer patients. In this context, we explored a pan-cancer panel in the investigation of germline variants in Brazilian patients presenting clinical criteria for hereditary cancer syndromes or familial history. METHODS: Seventy-one individuals diagnosed or with familial history of hereditary cancer syndromes were submitted to custom pan-cancer panel including 16 high and moderate penetrance genes previously associated with hereditary cancer syndromes (APC, BRCA1, BRCA2, CDH1, CDKN2A, CHEK2, MSH2, MSH6, MUTYH, PTEN, RB1, RET, TP53, VHL, XPA and XPC). All pathogenic variants were validated by Sanger sequencing. RESULTS: We identified a total of eight pathogenic variants among 12 of 71 individuals (16.9%). Among the mutation-positive subjects, 50% were diagnosed with breast cancer and had mutations in BRCA1, CDH1 and MUTYH. Notably, 33.3% were individuals diagnosed with polyposis or who had family cases and harbored pathogenic mutations in APC and MUTYH. The remaining individuals (16.7%) were gastric cancer patients with pathogenic variants in CDH1 and MSH2. Overall, 54 (76.05%) individuals presented at least one variant uncertain significance (VUS), totalizing 81 VUS. Of these, seven were predicted to have disease-causing potential. CONCLUSION: Overall, analysis of all these genes in NGS-panel allowed the identification not only of pathogenic variants related to hereditary cancer syndromes but also of some VUS that need further clinical and molecular investigations. The results obtained in this study had a significant impact on patients and their relatives since it allowed genetic counselling and personalized management decisions.

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Cervical cancer (CC) continues to be one of the leading causes of death for women across the world. Although it has been determined that papillomavirus infection is one of the main causes of the etiology of the disease, genetic and epigenetic factors are also required for its progression. Among the epigenetic factors are included the long noncoding RNAs (lncRNAs), transcripts of more than 200 nucleotides (nt) that generally do not code for proteins and have been associated with diverse functions such as the regulation of transcription, translation, RNA metabolism, as well as stem cell maintenance and differentiation, cell autophagy and apoptosis. Recently, studies have begun to characterize the aberrant regulation of lncRNAs in CC cells and tissues, including Homeobox transcript antisense RNA (HOTAIR), H19, Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), Cervical Carcinoma High-Expressed 1 (CCHE1), Antisense noncoding RNA in the inhibitors of cyclin-dependent kinase 4 (ANRIL), Growth arrest special 5 (GAS5) and Plasmacytoma variant translocation 1 (PVT1). They have been associated with several disease-related processes such as cell growth, cell proliferation, cell survival, metastasis and invasion as well as therapeutic resistance, and are novel potential biomarkers for diagnosis and prognosis in CC. In this review, we summarize the current literature regarding the knowledge we have about the roles and mechanisms of the lncRNAs in cervical neoplasia.

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Studies on the peopling of South America have been limited by the paucity of sequence data from Native Americans, especially from the east part of the Amazon region. Here, we investigate the whole exome variation from 58 Native American individuals (eight different populations) from the Amazon region and draw insights into the peopling of South America. By using the sequence data generated here together with data from the public domain, we confirmed a strong genetic distinction between Andean and Amazonian populations. By testing distinct demographic models, our analysis supports a scenario of South America occupation that involves migrations along the Pacific and Atlantic coasts. Occupation of the southeast part of South America would involve migrations from the north, rather than from the west of the continent.

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The aberrant expression of microRNAs in known to play a crucial role in carcinogenesis. Here, we evaluated the miRNA expression profile of sigmoid colon cancer (SCC) compared to adjacent-to-tumor (ADJ) and sigmoid colon healthy (SCH) tissues obtained from colon biopsy extracted from Brazilian patients. Comparisons were performed between each group separately, considering as significant p-values < 0.05 and |Log2(Fold-Change)| > 2. We found 20 differentially expressed miRNAs (DEmiRNAs) in all comparisons, two of which were shared between SCC vs. ADJ and SCC vs. SCH. We used miRTarBase, and miRTargetLink to identify target-genes of the differentially expressed miRNAs, and DAVID and REACTOME databases for gene enrichment analysis. We also used TCGA and GTEx databases to build miRNA-gene regulatory networks and check for the reproducibility in our results. As findings, in addition to previously known miRNAs associated with colorectal cancer, we identified three potential novel biomarkers. We showed that the three types of colon tissue could be clearly distinguished using a panel composed by the 20 DEmiRNAs. Additionally, we found enriched pathways related to the carcinogenic process in which miRNA could be involved, indicating that adjacent-to-tumor tissues may be already altered and cannot be considered as healthy tissues. Overall, we expect that these findings may help in the search for biomarkers to prevent cancer progression or, at least, allow its early detection, however, more studies are needed to confirm our results.

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Mild cognitive impairment (MCI) and Alzheimer's Disease (AD) are complex diseases with their molecular architecture not elucidated. APOE, Amyloid Beta Precursor Protein (APP), and Presenilin-1 (PSEN1) are well-known genes associated with both MCI and AD. Recently, epigenetic alterations and dysregulated regulatory elements, such as microRNAs (miRNAs), have been reported associated with neurodegeneration. In this study, differential expression analysis (DEA) was performed for genes and miRNAs based on microarray and RNA-Seq data. Global gene profile of healthy individuals, early and late mild cognitive impairment (EMCI and LMCI, respectively), and AD was obtained from ADNI Cohort. miRNA global profile of healthy individuals and AD patients was extracted from public RNA-Seq data. DEA performed with limma package on ADNI Cohort data highlighted eight differential expressed (DE) genes (AGER, LINC00483, MMP19, CATSPER1, ARFGAP1, GPER1, PHLPP2, TRPM2) (false discovery rate (FDR) p-value < 0.05) between EMCI and LMCI patients. Previous molecular studies showed associations between these genes with dementia and neurological-related pathways. Five dysregulated miRNAs were identified by DEA performed with RNA-Seq data and edgeR (FDR p-value < 0.002). All reported miRNAs in AD interact with the aforementioned genes. Our integrative transcriptomic analysis was able to identify a set of miRNA-gene interactions that may be involved in cognitive and neurodegeneration processes.

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Leprosy, which is caused by the human pathogen Mycobacterium leprae, causes nerve damage, deformity and disability in over 200,000 people every year. Because of the long doubling time of M. leprae (13 days) and the delayed onset of detectable symptoms, which is estimated to be approximately 3-7 years after infection, there is always a large percentage of subclinically infected individuals in the population who will eventually develop the disease, mainly in endemic countries. piRNAs comprise the largest group of small noncoding RNAs found in humans, and they are distinct from microRNAs (miRNAs) and small interfering RNAs (siRNAs). piRNAs function in transposon silencing, epigenetic regulation, and germline development. The functional role of piRNAs and their associated PIWI proteins have started to emerge in the development of human cancers and viral infections, but their relevance to bacterial diseases has not been investigated. The present study reports the piRNome of human skin, revealing that all but one of the piRNAs examined are downregulated in leprosy skin lesions. Considering that one of the best characterized functions of piRNAs in humans is posttranscriptional mRNA silencing, their functions are similar to what we have described for miRNAs, including acting on apoptosis, M. leprae recognition and engulfment, Schwann cell (SC) demyelination, epithelial-mesenchymal transition (EMT), loss of sensation and neuropathic pain. In addition to new findings on leprosy physiopathology, the discovery of relevant piRNAs involved in disease processes in human skin may provide new clues for therapeutic targets, specifically to control nerve damage, a prominent feature of leprosy that has no currently available pharmaceutical treatment.

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Circular RNAs (circRNAs) are a new class of long noncoding RNAs able to perform multiple functions, including sponging microRNAs (miRNAs) and RNA-Binding Proteins (RBPs). They play an important role in gastric carcinogenesis, but its involvement during gastric cancer (GC) development and progression are not well understood. We gathered miRNA and/or RBPs sponge circRNAs present in GC, and accessed their biological roles through functional enrichment of their target genes or ligand RBPs. We identified 54 sponge circRNAs in GC that are able to sponge 51 miRNAs and 103 RBPs. Then, we evaluated their host gene expression using The Cancer Genome Atlas (TCGA) database and observed that COL1A2 is the most overexpressed gene, which may be due to circHIPK3/miR-29b-c/COL1A2 axis dysregulation. We identified 27 GC-related pathways that may be affected mainly by circPVT1, circHIPK3 and circNF1. Our results indicate that circHIPK3/miR-107/BDNF/LIN28 axis may mediate chemoresistance in GC, and that circPVT1, circHIPK3, circNF1, ciRS-7 and circ_0000096 appear to be involved in gastrointestinal cancer development. Lastly, circHIPK3, circNRIP1 and circSMARCA5 were identified in different ethnic populations and may be ubiquitous modulators of gastric carcinogenesis. Overall, the studied sponge circRNAs are part of a complex RBP-circRNA-miRNA-mRNA interaction network, and are involved in the establishment, chemoresistance and progression of GC.

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INTRODUCTION: The nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil. METHODS: The entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa® (Viewer of Variants) software. RESULTS: Four NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high frequencies in both our study populations in comparison with other populations catalogued in the 1000 Genomes database. We also identified the NUDT15*4 haplotype in our study populations, at frequencies similar to those reported in other populations from around the world. CONCLUSION: Our findings indicate that Amerindian and admixed populations from northern Brazil have high frequencies of the NUDT15 haplotypes that alter the metabolism profile of thiopurines.

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