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1.
Mol Metab ; : 101987, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38977131

RESUMO

The advent of liquid biopsies presents a novel, minimally invasive methodology for the detection of disease biomarkers, offering a significant advantage over traditional biopsy techniques. Particularly, the analysis of cell-free RNA (cfRNA) has garnered interest due to its dynamic expression profiles and the capability to study various RNA species, including messenger RNA (mRNA) and long non-coding RNA (lncRNA). These attributes position cfRNA as a versatile biomarker with broad potential applications in clinical research and diagnostics. This review delves into the utility of cfRNA biomarkers as prognostic tools for obesity-related comorbidities, such as diabetes, dyslipidemia, and non-alcoholic fatty liver disease. We evaluate the efficacy of cfRNA in forecasting metabolic outcomes associated with obesity and in identifying patients likely to experience favorable clinical outcomes following bariatric surgery. Additionally, this review synthesizes evidence from studies examining circulating cfRNA across different physiological and pathological states, with a focus on its role in diabetes, including disease progression monitoring and treatment efficacy assessment. Through this exploration, we underscore the emerging relevance of cfRNA signatures in the context of obesity and its comorbidities, setting the stage for future investigative efforts in this rapidly advancing domain.

2.
Comput Struct Biotechnol J ; 23: 2289-2303, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38840832

RESUMO

The rapid progression of genomics and proteomics has been driven by the advent of advanced sequencing technologies, large, diverse, and readily available omics datasets, and the evolution of computational data processing capabilities. The vast amount of data generated by these advancements necessitates efficient algorithms to extract meaningful information. K-mers serve as a valuable tool when working with large sequencing datasets, offering several advantages in computational speed and memory efficiency and carrying the potential for intrinsic biological functionality. This review provides an overview of the methods, applications, and significance of k-mers in genomic and proteomic data analyses, as well as the utility of absent sequences, including nullomers and nullpeptides, in disease detection, vaccine development, therapeutics, and forensic science. Therefore, the review highlights the pivotal role of k-mers in addressing current genomic and proteomic problems and underscores their potential for future breakthroughs in research.

3.
Comput Struct Biotechnol J ; 23: 1919-1928, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38711760

RESUMO

The decrease in sequencing expenses has facilitated the creation of reference genomes and proteomes for an expanding array of organisms. Nevertheless, no established repository that details organism-specific genomic and proteomic sequences of specific lengths, referred to as kmers, exists to our knowledge. In this article, we present kmerDB, a database accessible through an interactive web interface that provides kmer-based information from genomic and proteomic sequences in a systematic way. kmerDB currently contains 202,340,859,107 base pairs and 19,304,903,356 amino acids, spanning 54,039 and 21,865 reference genomes and proteomes, respectively, as well as 6,905,362 and 149,305,183 genomic and proteomic species-specific sequences, termed quasi-primes. Additionally, we provide access to 5,186,757 nucleic and 214,904,089 peptide sequences absent from every genome and proteome, termed primes. kmerDB features a user-friendly interface offering various search options and filters for easy parsing and searching. The service is available at: www.kmerdb.com.

4.
Comput Struct Biotechnol J ; 23: 2011-2033, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38765606

RESUMO

The fields of Metagenomics and Metatranscriptomics involve the examination of complete nucleotide sequences, gene identification, and analysis of potential biological functions within diverse organisms or environmental samples. Despite the vast opportunities for discovery in metagenomics, the sheer volume and complexity of sequence data often present challenges in processing analysis and visualization. This article highlights the critical role of advanced visualization tools in enabling effective exploration, querying, and analysis of these complex datasets. Emphasizing the importance of accessibility, the article categorizes various visualizers based on their intended applications and highlights their utility in empowering bioinformaticians and non-bioinformaticians to interpret and derive insights from meta-omics data effectively.

5.
Bioessays ; 46(7): e2300210, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38715516

RESUMO

Understanding the influence of cis-regulatory elements on gene regulation poses numerous challenges given complexities stemming from variations in transcription factor (TF) binding, chromatin accessibility, structural constraints, and cell-type differences. This review discusses the role of gene regulatory networks in enhancing understanding of transcriptional regulation and covers construction methods ranging from expression-based approaches to supervised machine learning. Additionally, key experimental methods, including MPRAs and CRISPR-Cas9-based screening, which have significantly contributed to understanding TF binding preferences and cis-regulatory element functions, are explored. Lastly, the potential of machine learning and artificial intelligence to unravel cis-regulatory logic is analyzed. These computational advances have far-reaching implications for precision medicine, therapeutic target discovery, and the study of genetic variations in health and disease.


Assuntos
Sistemas CRISPR-Cas , Redes Reguladoras de Genes , Aprendizado de Máquina , Humanos , Sistemas CRISPR-Cas/genética , Biologia Computacional/métodos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Regulação da Expressão Gênica/genética , Animais , Elementos Reguladores de Transcrição/genética
6.
bioRxiv ; 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38712228

RESUMO

Genetic studies find hundreds of thousands of noncoding variants associated with psychiatric disorders. Massively parallel reporter assays (MPRAs) and in vivo transgenic mouse assays can be used to assay the impact of these variants. However, the relevance of MPRAs to in vivo function is unknown and transgenic assays suffer from low throughput. Here, we studied the utility of combining the two assays to study the impact of non-coding variants. We carried out an MPRA on over 50,000 sequences derived from enhancers validated in transgenic mouse assays and from multiple fetal neuronal ATAC-seq datasets. We also tested over 20,000 variants, including synthetic mutations in highly active neuronal enhancers and 177 common variants associated with psychiatric disorders. Variants with a high impact on MPRA activity were further tested in mice. We found a strong and specific correlation between MPRA and mouse neuronal enhancer activity including changes in neuronal enhancer activity in mouse embryos for variants with strong MPRA effects. Mouse assays also revealed pleiotropic variant effects that could not be observed in MPRA. Our work provides a large catalog of functional neuronal enhancers and variant effects and highlights the effectiveness of combining MPRAs and mouse transgenic assays.

7.
NAR Genom Bioinform ; 6(2): lqae029, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38584871

RESUMO

The prevalence of nucleic and peptide short sequences across organismal genomes and proteomes has not been thoroughly investigated. We examined 45 785 reference genomes and 21 871 reference proteomes, spanning archaea, bacteria, eukaryotes and viruses to calculate the rarity of short sequences in them. To capture this, we developed a metric of the rarity of each sequence in nature, the rarity index. We find that the frequency of certain dipeptides in rare oligopeptide sequences is hundreds of times lower than expected, which is not the case for any dinucleotides. We also generate predictive regression models that infer the rarity of nucleic and proteomic sequences across nature or within each domain of life and viruses separately. When examining each of the three domains of life and viruses separately, the R² performance of the model predicting rarity for 5-mer peptides from mono- and dipeptides ranged between 0.814 and 0.932. A separate model predicting rarity for 10-mer oligonucleotides from mono- and dinucleotides achieved R² performance between 0.408 and 0.606. Our results indicate that the mono- and dinucleotide composition of nucleic sequences and the mono- and dipeptide composition of peptide sequences can explain a significant proportion of the variance in their frequencies in nature.

8.
Front Immunol ; 15: 1362780, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487527

RESUMO

Dengue, caused by the dengue virus (DENV), affects millions of people worldwide every year. This virus has two distinct life cycles, one in the human and another in the mosquito, and both cycles are crucial to be controlled. To control the vector of DENV, the mosquito Aedes aegypti, scientists employed many techniques, which were later proved ineffective and harmful in many ways. Consequently, the attention shifted to the development of a vaccine; researchers have targeted the E protein, a surface protein of the virus and the NS1 protein, an extracellular protein. There are several types of vaccines developed so far, such as live attenuated vaccines, recombinant subunit vaccines, inactivated virus vaccines, viral vectored vaccines, DNA vaccines, and mRNA vaccines. Along with these, scientists are exploring new strategies of developing improved version of the vaccine by employing recombinant DNA plasmid against NS1 and also aiming to prevent the infection by blocking the DENV life cycle inside the mosquitoes. Here, we discussed the aspects of research in the field of vaccines until now and identified some prospects for future vaccine developments.


Assuntos
Vacinas contra Dengue , Vírus da Dengue , Dengue , Vacinas de DNA , Vacinas Virais , Animais , Humanos , Vírus da Dengue/genética , Mosquitos Vetores , Vacinas Atenuadas , Vacinas de Produtos Inativados
9.
Cancer Gene Ther ; 31(6): 861-870, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38351138

RESUMO

Early detection of cancer can significantly improve patient outcomes; however, sensitive and highly specific biomarkers for cancer detection are currently missing. Nullomers are the shortest sequences that are absent from the human genome but can emerge due to somatic mutations in cancer. We examine over 10,000 whole exome sequencing matched tumor-normal samples to characterize nullomer emergence across exonic regions of the genome. We also identify nullomer emerging mutational hotspots within tumor genes. Finally, we provide evidence for the identification of nullomers in cell-free RNA from peripheral blood samples, enabling detection of multiple tumor types. We show multiple tumor classification models with an AUC greater than 0.9, including a hepatocellular carcinoma classifier with an AUC greater than 0.99.


Assuntos
Ácidos Nucleicos Livres , Detecção Precoce de Câncer , Humanos , Detecção Precoce de Câncer/métodos , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Neoplasias/genética , Neoplasias/diagnóstico , Neoplasias/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Mutação , Sequenciamento do Exoma/métodos
11.
Nat Commun ; 15(1): 12, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195585

RESUMO

Frugivory evolved multiple times in mammals, including bats. However, the cellular and molecular components driving it remain largely unknown. Here, we use integrative single-cell sequencing (scRNA-seq and scATAC-seq) on insectivorous (Eptesicus fuscus; big brown bat) and frugivorous (Artibeus jamaicensis; Jamaican fruit bat) bat kidneys and pancreases and identify key cell population, gene expression and regulatory differences associated with the Jamaican fruit bat that also relate to human disease, particularly diabetes. We find a decrease in loop of Henle and an increase in collecting duct cells, and differentially active genes and regulatory elements involved in fluid and electrolyte balance in the Jamaican fruit bat kidney. The Jamaican fruit bat pancreas shows an increase in endocrine and a decrease in exocrine cells, and differences in genes and regulatory elements involved in insulin regulation. We also find that these frugivorous bats share several molecular characteristics with human diabetes. Combined, our work provides insights from a frugivorous mammal that could be leveraged for therapeutic purposes.


Assuntos
Quirópteros , Diabetes Mellitus , Humanos , Animais , Pâncreas , Rim , Células Epiteliais
12.
Eur J Cancer ; 196: 113421, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37952501

RESUMO

Early diagnosis of cancer can significantly improve survival of cancer patients; however sensitive and highly specific biomarkers for cancer detection are currently lacking for most cancer types. Nullpeptides are short peptides that are absent from the human proteome. Here, we examined the emergence of nullpeptides during cancer development. We analyzed 3,600,964 somatic mutations across 10,064 whole exome sequencing tumor samples spanning 32 cancer types. We analyze RNA-seq data from primary tumor samples to identify the subset of nullpeptides that emerge in highly expresed genes. We show that nullpeptides, and particularly the subset that is highly recurrent across cancer patients, can be identified in tumor biopsy samples. We find that cancer genes show an excess of nullpeptides and detect nullpeptide hotspots in specific loci of oncogenes and tumor suppressors. We also observe that recurrent nullpeptides are more likely to be found in neoantigens, which have been shown to be effective targets for immunotherapy, suggesting that they can be used to prioritize candidates. Our findings provide evidence for the utility of nullpeptides as cancer detection and therapeutic biomarkers.


Assuntos
Neoplasias , Humanos , Neoplasias/terapia , Oncogenes , Peptídeos/genética , Imunoterapia , Biomarcadores , Mutação , Antígenos de Neoplasias
13.
Nat Genet ; 56(1): 23-26, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38036782

RESUMO

The chemotherapeutic agent CX-5461, or pidnarulex, has been fast-tracked by the United States Food and Drug Administration for early-stage clinical studies of BRCA1-, BRCA2- and PALB2-mutated cancers. It is under investigation in phase I and II trials. Here, we find that, although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, nonselective, collateral mutagenesis in all three cell lines tested, to magnitudes that exceed known environmental carcinogens.


Assuntos
Mutagênicos , Neoplasias , Humanos , Mutagênicos/toxicidade , Proteína BRCA1/genética , Proteína BRCA2/genética , Benzotiazóis/uso terapêutico , Naftiridinas , Neoplasias/tratamento farmacológico
14.
Redox Biol ; 69: 102978, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38048653

RESUMO

Iodide plays a pivotal role in thyroid homeostasis due to its crucial involvement in thyroid hormone biosynthesis. Exposure to pharmacological doses of iodide elicits in the thyroid an autoregulatory response to preserve thyroid function, as well as an antioxidant response that is mediated by the Keap1/Nrf2 signaling pathway. The objective of the present study was to investigate the transcriptional response of the thyroid to excess iodide in a background of enhanced Nrf2 signaling. Keap1 knockdown (Keap1KD) mice that have activated Nrf2 signaling were exposed or not to excess iodide in their drinking water for seven days and compared to respective wild-type mice. RNA-sequencing of individual mouse thyroids identified distinct transcriptomic patterns in response to iodide, with Keap1KD mice showing an attenuated inflammatory response, altered thyroidal autoregulation, and enhanced cell growth/proliferative signaling, as confirmed also by Western blotting for key proteins involved in antioxidant, autoregulatory and proliferative responses. These findings underscore novel gene-environment interactions between the activation status of the Keap1/Nrf2 antioxidant response system and the dietary iodide intake, which may have implications not only for the goiter phenotype of Keap1KD mice but also for humans harboring genetic variations in KEAP1 or NFE2L2 or treated with Nrf2-modulating drugs.


Assuntos
Antioxidantes , Glândula Tireoide , Humanos , Camundongos , Animais , Antioxidantes/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Glândula Tireoide/metabolismo , Estresse Oxidativo , Iodetos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Interação Gene-Ambiente , Perfilação da Expressão Gênica , Homeostase
15.
bioRxiv ; 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-38045264

RESUMO

Massively parallel reporter assays (MPRAs) represent a set of high-throughput technologies that measure the functional effects of thousands of sequences/variants on gene regulatory activity. There are several different variations of MPRA technology and they are used for numerous applications, including regulatory element discovery, variant effect measurement, saturation mutagenesis, synthetic regulatory element generation or characterization of evolutionary gene regulatory differences. Despite their many designs and uses, there is no comprehensive database that incorporates the results of these experiments. To address this, we developed MPRAbase, a manually curated database that currently harbors 129 experiments, encompassing 17,718,677 elements tested across 35 cell types and 4 organisms. The MPRAbase web interface (http://www.mprabase.com) serves as a centralized user-friendly repository to download existing MPRA data for independent analysis and is designed with the ability to allow researchers to share their published data for rapid dissemination to the community.

16.
BMC Genomics ; 24(1): 768, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38087204

RESUMO

Early detection of human disease is associated with improved clinical outcomes. However, many diseases are often detected at an advanced, symptomatic stage where patients are past efficacious treatment periods and can result in less favorable outcomes. Therefore, methods that can accurately detect human disease at a presymptomatic stage are urgently needed. Here, we introduce "frequentmers"; short sequences that are specific and recurrently observed in either patient or healthy control samples, but not in both. We showcase the utility of frequentmers for the detection of liver cirrhosis using metagenomic Next Generation Sequencing data from stool samples of patients and controls. We develop classification models for the detection of liver cirrhosis and achieve an AUC score of 0.91 using ten-fold cross-validation. A small subset of 200 frequentmers can achieve comparable results in detecting liver cirrhosis. Finally, we identify the microbial organisms in liver cirrhosis samples, which are associated with the most predictive frequentmer biomarkers.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Cirrose Hepática , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Nível de Saúde , Metagenoma , Metagenômica , Sensibilidade e Especificidade
17.
Lung Cancer ; 186: 107424, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37979487

RESUMO

INTRODUCTION: NELSON and NLST prompted the implementation of lung cancer screening programs in the United States followed by several European countries. This study aimed to assess the sensitivity of different screening criteria among patients with lung cancer in Greece and investigate reasons for ineligibility. METHODS: We performed a retrospective analysis on patients with lung cancer referred to the largest referral center in Athens, Greece, between June 2014 and May 2023. The proportion of patients who would meet the updated USPSTF and NLST criteria was compared to the corresponding proportion of the Greek population over 15 years of age. RESULTS: Out of 2434 patients with lung cancer, 77.4 % (N = 1883) would meet the updated USPSTF criteria, and 58.9 % (N = 1439) would meet the NLST criteria at diagnosis; the corresponding proportions for the Greek population over 15 years would be 13.8 % and 8.2 %, respectively. Ineligible patients were more likely to be female, former or never-smokers, have adenocarcinoma histology, and have driver mutations (p < 0.001). CONCLUSIONS: Although the updated USPSTF criteria demonstrated good sensitivity, a substantial proportion of patients with lung cancer would still not be eligible for screening. Future studies to shape a comprehensive screening strategy should focus on the incorporation of additional risk factors for lung cancer, including air pollution and individual genetic susceptibility.


Assuntos
Neoplasias Pulmonares , Humanos , Feminino , Estados Unidos , Masculino , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/epidemiologia , Grécia/epidemiologia , Estudos Retrospectivos , Detecção Precoce de Câncer , Fumar/efeitos adversos , Programas de Rastreamento , Tomografia Computadorizada por Raios X
18.
Colloids Surf B Biointerfaces ; 231: 113584, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37837687

RESUMO

The spread of bacteria through contaminated surfaces is a major issue in healthcare, food industry, and other economic sectors. The widespread use of antibiotics is not a sustainable solution in the long term due to the development of antibiotic resistance. Therefore, surfaces with antibacterial properties have the potential to be a disruptive approach to combat microbial contamination. Different methods and approaches have been studied to impart or enhance antibacterial properties on surfaces. The surface roughness and texture are inherent parameters that significantly impact the antibacterial properties of a surface. They are also directly related to the previously employed machining and treatment methods. This review article discusses the correlation between surface roughness and antibacterial properties is presented and discussed. It begins with an introduction to the concepts of surface roughness and texture, followed by a description of the most commonly utilized machining methods and surface. A thorough analysis of bacterial adhesion and growth is then presented. Finally, the most recent studies in this research area are comprehensively reviewed. The studies are sorted and classified based on the utilized machining and treatment methods, which are divided into mechanical processes, surface treatments and coatings. Through the systematic review and record of the recent advances, the authors aim to assist and promote further research in this very promising and extremely important direction, by providing a systematic review of recent advances.


Assuntos
Antibacterianos , Bactérias , Antibacterianos/farmacologia , Aderência Bacteriana , Propriedades de Superfície
20.
Int J Mol Sci ; 24(7)2023 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-37047684

RESUMO

Cancer is one of the leading causes of death in the world; therefore, extensive research has been dedicated to exploring potential therapeutics, including immune checkpoint inhibitors (ICIs). Initially, programmed-death ligand-1 was the biomarker utilized to predict the efficacy of ICIs. However, its heterogeneous expression in the tumor microenvironment, which is critical to cancer progression, promoted the exploration of the tumor mutation burden (TMB). Research in various cancers, such as melanoma and lung cancer, has shown an association between high TMB and response to ICIs, increasing its predictive value. However, the TMB has failed to predict ICI response in numerous other cancers. Therefore, future research is needed to analyze the variations between cancer types and establish TMB cutoffs in order to create a more standardized methodology for using the TMB clinically. In this review, we aim to explore current research on the efficacy of the TMB as a biomarker, discuss current approaches to overcoming immunoresistance to ICIs, and highlight new trends in the field such as liquid biopsies, next generation sequencing, chimeric antigen receptor T-cell therapy, and personalized tumor vaccines.


Assuntos
Neoplasias Pulmonares , Melanoma , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Mutação , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/genética , Microambiente Tumoral/genética
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