Biology subjects

Fonseca, E.

Publications and source records attributed to Fonseca, E..

12 recordsLinked to original sources

bioRxiv2025

Unmasking Vibrio paracholerae: Genomic Reclassification and Epidemiology

The genus Vibrio encompasses globally relevant pathogens, of which Vibrio cholerae is the best known due to its role in cholera. Closely related species within the Cholerae clade--Vibrio paracholerae, Vibrio metoecus, and Vibrio tarriae--were long misclassified as non-O1/O139 V. cholerae. The objective of this study was to analyze all 13,000+ available V. cholerae genomes in GenBank to determine the presence of species from the Cholerae clade. Genome-wide analyses using Mash, Whole-genome based Average Nucleotide Identity (gANI), and digital DNA-DNA hybridization (dDDH) reclassified 193 unique genomes as V. paracholerae, while V. metoecus and V. tarriae were not identified. Phylogenomic analyses revealed that V. paracholerae forms distinct but relatively homogeneous lineages, spanning clinical, environmental, and animal sources over a period of more than a century. Virulence profiling revealed the absence of CTX and TCP; however, most genomes exhibited other virulence factors, including hemolysins, RTX toxins, colix toxin, and a conserved type VI secretion system. Resistome analysis revealed several antibiotic resistance genes, many of which were incorporated into superintegrons, highlighting the role of V. paracholerae as a reservoir of resistance determinants. Importantly, two genomic markers exhibited high discriminatory power for species identification, providing robust tools for epidemiological surveillance. These findings underscore the relevance of V. paracholerae for clinical and epidemiological monitoring.

genomics↗

bioRxiv2025

The application of metagenomics in the detection of arboviruses in mosquitoes (Diptera: Culicidade). A systematic review

Advances in deforestation and climate change directly imply changes in habits and the distribution of Culicidae across the globe, especially mosquitoes of medical importance and the main vectors of arboviruses. The viral metagenomics technique can be an important tool in characterizing the viral diversity present in mosquitoes. Thus, the aim was to identify evidence of the effectiveness of the viral metagenomics technique in detecting arboviruses in mosquitoes. This is a systematic review based on the PRISMA 2020 protocol. The research was carried out in five electronic databases: LILACS, PubMed, SciELO, Scopus and Web of Science, chosen to include studies published in health and interdisciplinary areas, as well as a complementary research on Google Scholar. Studies that used the viral metagenomics approach for the genomic evaluation of arboviruses found in mosquito samples were included, where the results demonstrated the presence of viral diversity and the identification of the genome of probable pathogenic viruses. The protocol was registered on the PROSPERO platform under the number CRD42024484713. 238 studies published in recent years were identified in the electronic databases. According to the inclusion/exclusion criteria, only 20 studies met the objectives for the systematic review. In all the studies, the viral metagenomics technique of genomic sequencing was applied to detect viruses, mainly those related to specific insect viruses, arboviruses, pathogenic viruses, animal viruses and plant viruses belonging to various viral families. Despite the challenges to be overcome in terms of the absence of reference sequences in genomic databases, the effectiveness of the metagenomics technique in characterizing the mosquito virome is clear from the studies, which broadens the understanding of viral diversity.

microbiology↗

bioRxiv2024

Vibrio mimicus carrying the Type III Secretion System 2 (T3SS2) and TDH toxin of Vibrio parahaemolyticus in an integrative conjugative element context

ObjectivesIdentify possible virulence factors in the genomes of Vibrio mimicus that may be determinants of diarrheal cases/outbreaks. MethodsAll V. mimicus genomes from Genbank were retrieved and the virulome was searched with Abricate using the VFDB database. Genomic islands (GIs) and integrative conjugative elements (ICEs) were identified using IslandViewer and ICEberg, respectively. ResultsFive ctx-negative V. mimicus genomes carrying the Type III Secretion System 2 (T3SS2) and the TDH/TRH toxin from Vibrio parahaemolyticus were identified. The T3SS-positive genomes presented the phylotypes T3SS2 and T3SS2{beta} and formed two clusters and one singleton throughout the V. mimicus phylogeny. Genomes carrying T3SS2 and T3SS2{beta} were associated with the tdh and trh genes, respectively. Furthermore, genomic analyses characterized an integrative conjugative element (ICE) with a size of [~]150 kb carrying both V. parahaemolyticus virulence determinants. ConclusionsIn addition to looking for cholera toxin genes in V. mimicus cases/outbreaks, it is important to consider V. parahaemolyticus toxins such as TDH and TRH. Furthermore, an ICE was identified and characterized in V. mimicus, being associated with T3SS2 and the TDH toxin, which is worrying, as it can disseminate these virulence factors among Vibrio spp.

genomics↗

bioRxiv2024

Cx43 Enhances Response to BRAF/MEK Inhibitors by Reducing DNA Repair Capacity

BRAF and MEK inhibitors (BRAF/MEKi) have radically changed the treatment landscape of advanced BRAF mutation-positive tumours. However, limited efficacy and emergence of drug resistance are major handicaps for successful treatments. Here, by using relevant preclinical models, we found that Connexin43 (Cx43), a protein that plays a role in cell-to-cell communication, increases effectiveness of BRAF/MEKi by recruiting DNA repair complexes to lamin-associated domains and promoting persistent DNA damage and cellular senescence. The nuclear compartmentalization promoted by Cx43 contributes to genome instability and synthetic lethality caused by excessive DNA damage, which could lead to a novel therapeutic approach for these tumours to overcome drug resistance. Based on these findings, we designed an innovative drug combination using small extracellular vesicles (sEVs) to deliver the full-Cx43 in combination with the BRAF/MEKi. This study reveals Cx43 as a new player on DNA repair and BRAF/MEKi response, underlining the therapeutical potential that this approach could eventually have in the clinic to overcome the limitations of current therapies and improve treatment outcomes for patients with advanced BRAF mutant tumours.

cancer biology↗

bioRxiv2024

Sequential and dynamic coding of water-sucrose categorization in rat gustatory cortices

The gustatory system enables our conscious perception of sweetness, allowing us to distinguish sweet solutions from water. However, the neural mechanisms underlying this categorization process in rats remain poorly understood. We addressed this question by designing a novel sucrose categorization task in which rats classified varying sucrose concentrations against water. We found that in the anterior insular cortex (aIC) and orbitofrontal cortex (OFC), neural activity primarily encoded the categorical distinction between sucrose and water, rather than specific sucrose concentrations. Notably, aIC neurons encoded this distinction faster than OFC neurons. Conversely, the OFC slightly preceded the aIC in encoding choice information, although both cortices maintained parallel encoding of the rats choices. The encoding of sensory and categorical decisions was dynamic and sequential, forming a sequence of encoding neurons throughout the trial. These findings reveal that sucrose categorization relies on dynamic coding sequences in the neuronal activity of the aIC and OFC rather than static, long-lasting (sustained) neural representations. This dynamic coding, supported by single-cell population decoding and principal component analyses, suggests that the brain continuously updates its representation of sucrose categorization as new information emerges. Additionally, both the aIC and OFC rapidly encoded reward outcomes. Our data supports the notion that gustatory cortices employ sequential and dynamic coding to compute sensorimotor transformations, from taste detection to categorical taste decisions and reward processing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/590344v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@20b8f0org.highwire.dtl.DTLVardef@4da81eorg.highwire.dtl.DTLVardef@586151org.highwire.dtl.DTLVardef@5d4469_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

In-depth analysis of Klebsiella aerogenes resistome, virulome and mobilome worldwide

Klebsiella aerogenes is an emergent pathogen associated with outbreaks of carbapenem-resistant strains. To date, studies focusing on K. aerogenes have been small-scale and/or geographically restricted. Here, we analyzed the epidemiology, resistome, virulome, and mobilome of this species based on 561 genomes, spanning all continents. Furthermore, we sequenced four new strains from Brazil (mostly from the Amazon region). Dozens of STs occur worldwide, but the pandemic clones ST93 and ST4 have prevailed in several countries. Almost all genomes were clinical, however, most of them did not carry ESBL or carbapenemases, instead, they carried chromosomal alterations (omp36, ampD, ampG, ampR) associated with resistance to {beta}-lactams. Integrons were also identified, presenting gene cassettes not yet reported in this species (blaIMP, blaVIM, blaGES). Considering the virulence loci, the yersiniabactin and colibactin operons were found in the ICEKp10 element, which is disseminated in genomes of several STs, as well as an incomplete salmochelin cluster. In contrast, the aerobactin hypervirulence trait was observed only in one ST432 genome. Plasmids were common, mainly from the ColRNAI replicon, with some carrying resistance genes (mcr, blaTEM, blaNDM, blaIMP, blaKPC, blaVIM) and virulence genes (EAST1, senB). Interestingly, plasmids containing the colicin gene occurred in hundreds of genomes of different STs.

genomics↗

bioRxiv2023

Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. We investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats using various techniques. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induced greater weight loss in obese than lean rats, which was associated with changes in LH ensemble activity. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensines food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensines appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.

neuroscience↗

bioRxiv2023

Genomic characterization of a pandrug-resistant Klebsiella pneumoniae belonging to the high-risk ST11 in the Brazilian Amazon region

Pandrug-resistant (PDR) K. pneumoniae has been reported sporadically in many countries and remains rare in Brazil. The lack of genomic studies limits the comprehension of the determinants mostly involved with the PDR emergence in K. pneumoniae. This study aimed to unravel the main genetic determinants involved with the PDR background of a clinical ST11 K. pneumoniae recovered in the Brazilian Amazon region. The carbapenem-resistant Kp196 was submitted to WGS and its intrinsic and acquired resistome was assessed by CARD and comparison with wild-type genes. Kp196 resistome was composed of acquired resistance determinants and mutations in chromosomal genes. Among the formers, blaCTX-M-15 and blaNDM-1, blaOXA-9, blaOXA-1, aadA1, aacA4, strAB, aph(3)-VI, aac(3)-IId, qnrS1, qnrB1, oqxAB, dfrA14, sul2, catB3 were found in the vicinity of mobile genetic elements, which could contribute to their spread. Kp196 colistin resistance was multifactorial and attributed to modifications in ArnT (M114L/V117I/R372K), PhoQ (D150G), and the mgrB disruption by ISKpn25. Besides the presence of qnr and oqxAB genes, Kp196 also presented altered GyrA (S83I) and ParC (S80I). An in-block deletion in the repressor RamR, contributing to acrAB overexpression, and the presence of an enhanced-function AcrB variant (S966A), probably led to the Kp196 multidrug and tigecycline resistance. Insertions, in-block deletion, and missense mutations were involved with ompK35-36-37 inactivation, also accounting for the Kp196 multidrug resistance, including carbapenems. The Kp196 PDR profile, especially the carbapenem resistance, was due to the accumulation of different mechanisms, in which modifications in housekeeping genes accounted for a more stable resistome.

genomics↗

bioRxiv2022

Global genomic epidemiology, resistome, virulome and plasmidome of the Extraintestinal Pathogenic Escherichia coli (ExPEC) ST38 lineage

Most of the extraintestinal human infections worldwide are determined by some specific Extraintestinal Pathogenic Escherichia coli (ExPEC) lineages, which also present a zoonotic character. One of these lineages belongs to ST38, which is considered a uropathogenic/enteroaggregative E. coli hybrid and a high-risk globally disseminated ExPEC. To get insights on the aspects of ST38 epidemiology and evolution as a multidrug resistant and pathogenic lineage, this study performed a global comparative genomic analysis on ST38 genomes. A total of 376 genomes recovered from environments, humans, livestock, wild and domestic animals in all continents throughout three decades were analyzed considering the ST38 phylogenomics, resistome, plasmidome, and virulome. In general, our analyses revealed that, independently of host sources and geographic origin, these genomes were distributed in two clusters comprising clonal and non-clonal genomes. Moreover, the ST38 accessory genome was not strictly associated with clusters and sub-clusters. Interestingly, the High Pathogenicity Island (HPI) prevailed in the major cluster (cluster 2), which comprised most of the genomes from human origin recovered worldwide (2000 to 2020). In addition, the ExPEC ST38 harbors a huge and diverse plasmidome that might contribute to the evolution of this lineage, reflecting in ST38 ability to live in a diversity of niches as a commensal or pathogenic organism.

genomics↗

bioRxiv2019

Senolytic activity of small molecular polyphenols from olive restores chondrocyte redifferentiation and cartilage regeneration in osteoarthritis

Osteoarthritis (OA) is the most prevalent disorder of articulating joints and a leading cause of disability in humans, affecting half of the worlds population aged 65 years or older. Articular cartilage and synovial tissue from OA patients show an overactivity of the membrane channel protein connexin43 (Cx43) and accumulation of senescent cells associated with disrupted tissue regeneration. We have recently demonstrated the use of the Cx43 as an appropriate therapeutic target to halt OA progression by decreasing the accumulation of senescent cells and by triggering redifferentiation of osteoarthritic chondrocytes (OACs) into a more differentiated state, restoring the fully mature phenotype and cartilage regeneration. In this study we have found that small molecular polyphenols derived by olive extracts target Cx43 and senescence in OACs, synovial and bone cells from patients and in human mesenchymal stem cells (hMSCs). Our results indicate that these small molecules including oleuropein regulate the promoter activity of Cx43 gene. The downregulation of Cx43 expression by oleuropein reduce gap junction intercellular communication, cellular senescence in chondrocytes and enhance the propensity of hMSCs to differentiate into chondrocytes and bone cells, reducing adipogenesis. In concordance with these results, these small molecules reduce Cx43 and decrease Twist-1 activity leading to redifferentiation of OACs, which restores the synthesis of cartilage ECM components (Col2A1 and proteoglycans) and reduces inflammatory and catabolic factors IL-1{beta}, IL-6, COX-2 and MMP-3 and cellular senescence orchestrated by p53/p21 together with the synthesis of SASP via NF-kB. Altogether, our results demonstrate the use of the olive-derived polyphenols such as oleuropein as potentially effective therapeutic agents to enhance the efficacy of hMSC therapy and to induce a pro-regenerative environment in OA patients by restoring cellular phenotype and clearing out senescent cells in joint tissues in order to stop or prevent the progression of the disease.

cell biology↗

bioRxiv2018

Sucrose Intensity coding and decision-making in taste cortices

Sucroses sweet intensity is one attribute contributing to the overconsumption of high-energy palatable foods. However, it is not known how sucrose intensity is encoded and used to make perceptual decisions by neurons in taste-sensitive cortices. We trained rats in a sucrose intensity discrimination task and found that sucrose evoked a widespread response in neurons recorded in posterior-Insula (pIC), anterior-Insula (aIC), and Orbitofrontal cortex (OFC). Remarkably, only a few Intensity-selective neurons conveyed the most information about sucroses intensity, indicating that for sweetness the gustatory system used a compact and distributed code. Sucrose intensity was encoded in both firing-rates and spike-timing. The pIC, aIC, and OFC neurons tracked movement direction, with OFC neurons yielding the most robust response. aIC and OFC neurons encoded the subjects choices, whereas all three regions tracked reward omission. Overall, these multimodal areas provide a neural representation of perceived sucrose intensity, and of task-related information underlying perceptual decision-making.

neuroscience↗

bioRxiv2018

Expansion, retention and loss in the Acyl-CoA Synthetase \"Bubblegum\" (Acsbg) gene family in vertebrate history

AO_SCPLOWBSTRACTC_SCPLOWFatty acids (FAs) constitute a considerable fraction of all lipid molecules with a fundamental role in numerous physiological processes. In animals, the majority of complex lipid molecules are derived from the transformation of FAs through several biochemical pathways. Yet, for FAs to enroll in these pathways they require an activation step. FA activation is catalyzed by the rate limiting action of Acyl-CoA synthases. Several Acyl-CoA enzyme families have been previously described and classified according to the chain length of FA they process. Here, we address the evolutionary history of the ACSBG gene family which activates, FA with more than 16 carbons. Currently, two different ACSBG gene families, ACSBG1 and ACSBG2, are recognized in vertebrates. We provide evidence that a wider and unequal ACSBG gene repertoire is present in vertebrate lineages. We identify a novel ACSBG-like gene lineage which occurs specifically in amphibians, ray finned fish, coelacanths and chondrichthyes named ACSBG3. Also, we show that the ACSBG2 gene lineage duplicated in the Theria ancestor. Our findings, thus offer a far richer understanding on FA activation in vertebrates and provide key insights into the relevance of comparative and functional analysis to perceive physiological differences, namely those related with lipid metabolic pathways.

genetics↗