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Papers by Marcelo Ribeiro-Alves

PLOS ONE

The Human Immunodeficiency Virus Type I (HIV-1) subtype B comprises approximately 10% of all HIV ... more The Human Immunodeficiency Virus Type I (HIV-1) subtype B comprises approximately 10% of all HIV infections in the world. The HIV-1 subtype B epidemic comprehends a pandemic variant (named BPANDEMIC) disseminated worldwide and non-pandemic variants (named BCAR) that are mostly restricted to the Caribbean. The goal of this work was the identification of amino acid signatures (AAs) characteristic to the BCAR and BPANDEMIC variants. To this end, we analyzed HIV-1 subtype B full-length (n = 486) and partial (n = 814) genomic sequences from the Americas classified within the BCAR and BPANDEMIC clades and reconstructed the sequences of their most recent common ancestors (MRCA). Analysis of contemporary HIV-1 sequences revealed 13 AAs between BCAR and BPANDEMIC variants (four on Gag, three on Pol, three on Rev, and one in Vif, Vpu, and Tat) of which only two (one on Gag and one on Pol) were traced to the MRCA. All AAs correspond to polymorphic sites located outside essential functional proteins domains, except the AAs in Tat. The absence of stringent AAs inherited from their ancestors between modern BCAR and BPANDEMIC variants support that ecological factors, rather than viral determinants, were the main driving force behind the successful spread of the BPANDEMIC strain.

Abstract: Benthic macroinvertebrates Functional Feeding Group (FFG) have been used to determine a... more Abstract: Benthic macroinvertebrates Functional Feeding Group (FFG) have been used to determine aquatic assemblage dynamics and as a biomonitoring tool. The main goals of this study were to assess the effects of stream variables on the abundance and richness of FFGs and evaluate ecosystem attributes (FFG ratios) as a tool to assess ecological conditions of Atlantic Rainforest streams. We sampled 146 sites with different impairment conditions in Rio de Janeiro, Brazil. Richness was significantly different among impairment conditions for all FFGs. Mixed-effect models show that aquatic macroinvertebrate FFGs differed in their responses to abiotic variables for abundance and richness. Also, they were reduced in the impaired sites when compared to intermediate and reference sites. The FFG ratio indicated significant differences along the impairment gradient. The FFG ratio analysis was shown to be a fast and cheap tool that can be used for monitoring aquatic ecosystems in the Atlantic For...

Revista Científica da Faculdade de Medicina de Campos

Hashimoto’s thyroiditis (HT) is an autoimmune and inflammatory disease in which antibodies are di... more Hashimoto’s thyroiditis (HT) is an autoimmune and inflammatory disease in which antibodies are directed against the thyroid gland leading to chronic inflammation and hypothyroidism. The autoimmunity against thyroid antigens can be associated to genetic background and environmental factors. Thyroid peroxidase (TPO) and thyroglobulin (TG) are the major autoantigens for characterizing the disease. HT is related to the activation of autoreactive CD4+ T cells, CD8+ cytotoxic T cells and antithyroid antibody producing-B cells. Among several cytokines related to the pathogenesis of HT, a proliferation-inducing ligand (APRIL) has been studied in the context of the establishment and/or maintenance of autoimmune diseases. The role of APRIL in the pathogenesis of HT is still poorly understood. Therefore, the present study aimed to compare APRIL serum concentration in HT patients and healthy donors by ELISA. We observed a significant decrease in APRIL concentration in HT patients when compared ...

Neuroimmunomodulation

Introduction: IL-1β, a cytokine from the innate immune response, is well known for its proinflamm... more Introduction: IL-1β, a cytokine from the innate immune response, is well known for its proinflammatory effects and stimulating activity on the hypothalamus-pituitary-adrenal axis, leading to the pituitary synthesis of adrenocorticotropic hormone followed by cortisol (and dehydroepiandrosterone – DHEA) release by the adrenal gland. While IL-1β modulates the adrenal steroidogenesis at the central level, it is unclear whether it also exerts an effect on the adrenal gland. Method: We studied the effect of IL-1β on adrenal steroid production and steroidogenic enzyme RNA expression in the human cell line NCI-H295R. We also explored eventual changes in the microRNA (miRNA) profile from IL-1β-treated NCI-H295R cells. Results: Transcripts encoding IL-1β receptors 1 and 2 were noticeable in the cell line, with cortisol and DHEA production showing a subtle increase after cytokine treatment. Transcripts from key enzymes in the steroidogenic pathway were analyzed, with no noticeable changes on t...

Medicine

Abstract Sarcoidosis is a multi-systemic granulomatous disease. Affected individuals can show spo... more Abstract Sarcoidosis is a multi-systemic granulomatous disease. Affected individuals can show spontaneous healing, develop remission with drug treatment within 2 years, or become chronically ill. Our main goal was to identify features that are related to prognosis. The study consisted of 101 patients, recruited at a single center, who were already diagnosed with sarcoidosis at the start of the study or were diagnosed within 48 months. Ninety individuals were followed-up for at least 24 months and were classified according to clinical outcome status (COS 1 to 9). Those with COS 1–4 and COS 5–9 were classified as having favorable and unfavorable outcomes, respectively. Unconditional logistic regression analyses were conducted to define which variables were associated with sarcoidosis outcomes. Subsequently, we established a scoring system to help predict the likelihood of a favorable or unfavorable outcome. Of our patients, 48% developed a chronic form of the disease (COS 5–9). Three clinical features were predictive of prognosis in sarcoidosis. We built a score-based model where the absence of rheumatological markers (1 point), normal pulmonary functions (2 points), and the presence of early respiratory symptoms manifestations (2 points) were associated with a favorable prognosis. We predicted that a patient with a score of 5 had an 86% (95% confidence interval [CI] 74%–98%) probability of having a favorable prognosis, while those with scores of 4, 3, 2, 1, and 0 had probabilities of 72% (95% CI 59–85%), 52% (95% CI 40–63%), 31% (95% CI 17–44%), 15% (95% CI 2–28%), and 7% (95% CI 0–16%) of having a favorable prognosis, respectively. Thus, our easy-to-compute algorithm can help to predict prognosis of sarcoidosis patients, facilitating their management.

BMC Infectious Diseases

Background Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwid... more Background Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwide. In some TB-HIV co-infected individuals treated for both diseases simultaneously, a pathological inflammatory reaction termed immune reconstitution inflammatory syndrome (IRIS) may occur. The risk factors for IRIS are not fully defined. We investigated the association of HLA-B, HLA-C, and KIR genotypes with TB, HIV-1 infection, and IRIS onset. Methods Patients were divided into four groups: Group 1- TB+/HIV+ (n = 88; 11 of them with IRIS), Group 2- HIV+ (n = 24), Group 3- TB+ (n = 24) and Group 4- healthy volunteers (n = 26). Patients were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. The HLA-B and HLA-C loci were typed using SBT, NGS, and KIR genes by PCR-SSP. Unconditional logistic regression models were performed for Protection/risk estimation. Results Among the individuals with TB as the outcome, KIR2DS2 was associated with increased risk for TB ons...

International Journal of Scientific Reports

Several variants involved in the expression of proteins related to immunopathological mechanisms ... more Several variants involved in the expression of proteins related to immunopathological mechanisms have been associated with dengue, but few specifically related to severe dengue. In addition, children are a group with a high incidence and mortality rate due to dengue. Several immunopathological processes developed specifically in children affected with severe dengue partially explain this risk condition. This case-control retrospective study aimed to examine the association of variants in CD209, NFKBIA, IL12B, and IL1B genes with severe dengue. These genes encode proteins involved in one of the main pathways of the immune response against dengue virus infection. The study population included affected children and householding controls from Brazil. Genotyping was performed with Real-Time TaqMan assays, and the association analysis was performed with conditional logistic regressions. We found the IL1B rs1143634 genotypes carrying the T allele to be associated with susceptibility to sev...

Journal of Epidemiology and Community Health

BackgroundThe novel coronavirus (SARS-CoV-2) is a global pandemic. The lack of protective vaccine... more BackgroundThe novel coronavirus (SARS-CoV-2) is a global pandemic. The lack of protective vaccine or treatment led most of the countries to follow the flattening of the infection curve with social isolation measures. There is evidence that socioeconomic inequalities have been shaping the COVID-19 burden among low and middle-income countries. This study described what sociodemographic and socioeconomic factors were associated with the greatest risk of COVID-19 infection and mortality and how did the importance of key neighbourhood-level socioeconomic factors change over time during the early stages of the pandemic in the Rio de Janeiro municipality, Brazil.MethodsWe linked socioeconomic attributes to confirmed cases and deaths from COVID-19 and computed age-standardised incidence and mortality rates by domains such as age, gender, crowding, education, income and race/ethnicity.ResultsThe evidence suggests that although age-standardised incidence rates were higher in wealthy neighbour...

Scientific Reports

Capsid proteins often present a positively charged arginine-rich sequence at their terminal regio... more Capsid proteins often present a positively charged arginine-rich sequence at their terminal regions, which has a fundamental role in genome packaging and particle stability for some icosahedral viruses. These sequences show little to no conservation and are structurally dynamic such that they cannot be easily detected by common sequence or structure comparisons. As a result, the occurrence and distribution of positively charged domains across the viral universe are unknown. Based on the net charge calculation of discrete protein segments, we identified proteins containing amino acid stretches with a notably high net charge (Q > + 17), which are enriched in icosahedral viruses with a distinctive bias towards arginine over lysine. We used viral particle structural data to calculate the total electrostatic charge derived from the most positively charged protein segment of capsid proteins and correlated these values with genome charges arising from the phosphates of each nucleotide. ...

PLOS Neglected Tropical Diseases

Leprosy urgently needs a precise and early diagnostic tool. The sensitivity of the direct (bacill... more Leprosy urgently needs a precise and early diagnostic tool. The sensitivity of the direct (bacilli staining, Mycobacterium leprae DNA) and indirect (antibody levels, T cell assays) diagnostics methods vary based on the clinical form. Recently, PCR-based M. leprae DNA detection has been shown to differentially diagnose leprosy from other dermatological conditions. However, accuracy can still be improved, especially for use with less invasive clinical samples. We tested different commercial DNA extraction kits: DNeasy Blood & Tissue, QIAamp DNA Microbiome, Maxwell 16 DNA Purification, PowerSoil DNA Isolation; as well as in-house phenol-chloroform and Trizol/FastPrep methods. Extraction was performed on M. leprae-infected mouse footpads and different clinical samples of leprosy patients (skin biopsies and scrapings, lesion, oral and nasal swabs, body hair, blood on FTA cards, peripheral whole blood). We observed that the Microbiome kit was able to enrich for mycobacterial DNA, most likely due the enzymatic digestion cocktail along with mechanical disruption involved in this method. Consequently, we had a significant increase in sensitivity in skin biopsies from paucibacillary leprosy patients using a duplex qPCR targeting 16S rRNA (M. leprae) and 18S rRNA (mammal) in the StepOnePlus system. Our data showed that the presence of M. leprae DNA was best detected in skin biopsies and skin scrapings, independent of the extraction method or the clinical form. For multibacillary patients, detection of M. leprae DNA in nasal swabs indicates the possibility of having a much less invasive sample that can be used for the purposes of DNA sequencing for relapse analysis and drug resistance monitoring. Overall, DNA extracted with the Microbiome kit presented the best bacilli detection rate for paucibacillary cases, indicating that investments in extraction methods with mechanical and DNA digestion should be made.

RNA Biology

ABSTRACT We investigated the gene-expression variation among humans by analysing previously publi... more ABSTRACT We investigated the gene-expression variation among humans by analysing previously published mRNA-seq and ribosome footprint profiling of heart left-ventricles from healthy donors. We ranked the genes according to their coefficient of variation values and found that the top 5% most variable genes had special features compared to the rest of the genome, such as lower mRNA levels and shorter half-lives coupled to increased translation efficiency. We observed that these genes are mostly involved with immune response and have a pleiotropic effect on disease phenotypes, indicating that asymptomatic conditions contribute to the gene expression diversity of healthy individuals.

Scientific Reports

Neutrophil extracellular traps (NETs) emerge from the cell as a DNA scaffold associated with cyto... more Neutrophil extracellular traps (NETs) emerge from the cell as a DNA scaffold associated with cytoplasmic and granular proteins, able to immobilize and kill pathogens. This association occurs following nuclear and granular membrane disintegration, allowing contact with the decondensed chromatin. Thus, it is reasonable to speculate that the DNA can also mix with miRNAs and carry them in NETs. Here, we report for the first time the presence of the miRNA carriers associated with NETs and miRNAs present in NET-enriched supernatants (NET-miRs), thus adding a novel class of molecules and new proteins that can be released and transported in the NET platform. We observed that the majority of NET-miRs were common to all four stimuli used (PMA, interleukin-8, amyloid fibrils and Leishmania), and that miRNA-142-3p carried by NETs down-modulates protein kinase Cα and regulates TNF-α production in macrophages upon NET interaction with these cells. Our findings unveil a novel role for NETs in the ...

mBio

In tuberculosis (TB), as in other infectious diseases, studies of small noncoding RNAs (sncRNA) i... more In tuberculosis (TB), as in other infectious diseases, studies of small noncoding RNAs (sncRNA) in peripheral blood have focused on microRNAs (miRNAs) but have neglected the other major sncRNA classes in spite of their potential functions in host gene regulation. Using RNA sequencing of whole blood, we have therefore determined expression of miRNA, PIWI-interacting RNA (piRNA), small nucleolar RNA (snoRNA), and small nuclear RNA (snRNA) in patients with TB (n = 8), latent TB infection (LTBI; n = 21), and treated LTBI (LTBItt; n = 6) and in uninfected exposed controls (ExC; n = 14). As expected, sncRNA reprogramming was greater in TB than in LTBI, with the greatest changes seen in miRNA populations. However, substantial dynamics were also evident in piRNA and snoRNA populations. One miRNA and 2 piRNAs were identified as moderately accurate (area under the curve [AUC] = 0.70 to 0.74) biomarkers for LTBI, as were 1 miRNA, 1 piRNA, and 2 snoRNAs (AUC = 0.79 to 0.91) for accomplished LTB...

Journal of Clinical Microbiology

Pleural tuberculosis (PlTB), a common form of extrapulmonary TB, remains as a challenge in the di... more Pleural tuberculosis (PlTB), a common form of extrapulmonary TB, remains as a challenge in the diagnosis among many causes of pleural effusion. We recently reported that the combinatorial analysis of interferon-gamma (IFN-γ), IFN-γ-inducible protein 10 (IP-10), and adenosine deaminase (ADA) from the pleural microenvironment was useful to distinguish pleural effusion caused by TB (microbiologically or not confirmed cases) among other etiologies. In this cross-sectional cohort study, a set of inflammatory mediators was quantified in blood and pleural fluid (PF) from exudative pleural effusion cases, including PlTB (n = 27) and non-PlTB (nTB; n = 25) patients. The levels of IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF, IP-10, TGF-β1, and ADA were determined using cytometric bead assay, ELISA or biochemical tests. IFN-γ, IP-10, TNF, TGF-β, and ADA quantified in PF showed significantly higher concentrations in PlTB patients when compared to nTB. When blood and PF were compared, we have id...

BMC Infectious Diseases

Background: The major factors contributing for nerve damage and permanent disabilities in leprosy... more Background: The major factors contributing for nerve damage and permanent disabilities in leprosy are type 1 or reversal reactions (RR) and type 2 or erythema nodosum leprosum (ENL). Gene profiling of leprosy reactions have shown that different pathways are activated during the course of reactions, which is consistent with the exacerbated immune response exhibited by these patients. Methods: We used qPCR to screen a panel of 90 genes related to the immune response in leprosy in RNA-derived peripheral leukocytes of patients with (N = 94) and without leprosy reactions (N = 57) in order to define expression signatures correlated to RR or ENL. Results: Our results show that there is a marked signature for RR in the blood, comprising genes mostly related to the innate immune responses, including type I IFN components, autophagy, parkins and Toll like receptors. On the other hand, only Parkin was differentially expressed in the ENL group. Conclusions: The data put together corroborates previous work that brings evidence that an acute uncontrolled exacerbated immune response designed to contain the spread of M. leprae antigens might be cause of RR pathogenesis. Identifying a blood profile useful to predict leprosy reactions prior to its development might help to reduce the morbidity associated to this disabling disease.

BackgroundHost factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Inte... more BackgroundHost factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Interferons have been reported as the main antiviral factor in Zika and other flavivirus infections.MethodsWe accessed samples from Zika pregnancies, conducted a case-control study to verify whether interferon alfa receptor 1 (IFNAR1) and interferon lambda 2 and 4 (IFNL2/4) single nucleotide polymorphisms (SNPs) contribute to CZS newborn outcome and we characterized placenta gene expression profile at term.FindingsNewborns carrying CG/CC genotypes of rs2257167 inIFNAR1presented higher risk of developing CZS (OR=3.73; IC=1.36-10.21;Pcorrected=0.02646). No association betweenIFNLSNPs and CZS was observed. Placenta from CZS cases displayed lower levels ofIFNL2andISG15along with higherIFIT5.The rs2257167 CG/CC placentas also demonstrated high levels ofIFIT5and inflammation-related genes.InterpretationWe found CZS to be related with exacerbated type I IFN and insufficient type III IFN in placenta...

BMC Genomics

Background: Citrus are among the most important crops in the world. However, there are many disea... more Background: Citrus are among the most important crops in the world. However, there are many diseases that affect Citrus caused by different pathogens. Citrus also hosts many symbiotic microorganisms in a relationship that may be advantageous for both organisms. The fungi Phyllosticta citricarpa, responsible for citrus black spot, and Phyllosticta capitalensis, an endophytic species, are examples of closely related species with different behavior in citrus. Both species are always biologically associated and are morphologically very similar, and comparing their genomes could help understanding the different lifestyles. In this study, a comparison was carried to identify genetic differences that could help us to understand the biology of P. citricarpa and P. capitalensis. Results: Drafts genomes were assembled with sizes close to 33 Mb for both fungi, carrying 15,206 and 14,797 coding sequences for P. citricarpa and P. capitalensis, respectively. Even though the functional categories of these coding sequences is similar, enrichment analysis showed that the pathogenic species presents growth and development genes that may be necessary for the pathogenicity of P. citricarpa. On the other hand, family expansion analyses showed the plasticity of the genome of these species. Particular families are expanded in the genome of an ancestor of P. capitalensis and a recent expansion can also be detected among this species. Additionally, evolution could be driven by environmental cues in P. citricarpa. Conclusions: This work demonstrated genomic differences between P. citricarpa and P. capitalensis. Although the idea that these differences could explain the different lifestyles of these fungi, we were not able to confirm this hypothesis. Genome evolution seems to be of real importance among the Phyllosticta isolates and it is leading to different biological characteristics of these species.

Journal of Cerebral Blood Flow & Metabolism

Oxidative stress and chronic inflammation in arterial walls have been implicated in intracranial ... more Oxidative stress and chronic inflammation in arterial walls have been implicated in intracranial aneurysm (IA) formation and rupture. Dimethyl fumarate (DMF) exhibits immunomodulatory properties, partly via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which reduces oxidative stress by inducing the antioxidant response element (ARE). This study evaluated the effects of DMF both in vitro, using tumor necrosis factor (TNF)-α-treated vascular smooth muscle cells (VSMC), and in vivo, using a murine elastase model to induce aneurysm formation. The mice were treated with either DMF at 100 mg/kg/day P.O. or vehicle for two weeks. DMF treatment protected VSMCs from TNF-α-induced inflammation as demonstrated by its downregulation of cytokines and upregulation of Nrf2 and smooth muscle cell markers. At higher doses, DMF also inhibited the pro-proliferative action of TNF-α by increasing apoptosis which protected the cells from aponecrosis. In mice, DMF treatment ...

PLOS ONE

The Human Immunodeficiency Virus Type I (HIV-1) subtype B comprises approximately 10% of all HIV ... more The Human Immunodeficiency Virus Type I (HIV-1) subtype B comprises approximately 10% of all HIV infections in the world. The HIV-1 subtype B epidemic comprehends a pandemic variant (named BPANDEMIC) disseminated worldwide and non-pandemic variants (named BCAR) that are mostly restricted to the Caribbean. The goal of this work was the identification of amino acid signatures (AAs) characteristic to the BCAR and BPANDEMIC variants. To this end, we analyzed HIV-1 subtype B full-length (n = 486) and partial (n = 814) genomic sequences from the Americas classified within the BCAR and BPANDEMIC clades and reconstructed the sequences of their most recent common ancestors (MRCA). Analysis of contemporary HIV-1 sequences revealed 13 AAs between BCAR and BPANDEMIC variants (four on Gag, three on Pol, three on Rev, and one in Vif, Vpu, and Tat) of which only two (one on Gag and one on Pol) were traced to the MRCA. All AAs correspond to polymorphic sites located outside essential functional proteins domains, except the AAs in Tat. The absence of stringent AAs inherited from their ancestors between modern BCAR and BPANDEMIC variants support that ecological factors, rather than viral determinants, were the main driving force behind the successful spread of the BPANDEMIC strain.

Abstract: Benthic macroinvertebrates Functional Feeding Group (FFG) have been used to determine a... more Abstract: Benthic macroinvertebrates Functional Feeding Group (FFG) have been used to determine aquatic assemblage dynamics and as a biomonitoring tool. The main goals of this study were to assess the effects of stream variables on the abundance and richness of FFGs and evaluate ecosystem attributes (FFG ratios) as a tool to assess ecological conditions of Atlantic Rainforest streams. We sampled 146 sites with different impairment conditions in Rio de Janeiro, Brazil. Richness was significantly different among impairment conditions for all FFGs. Mixed-effect models show that aquatic macroinvertebrate FFGs differed in their responses to abiotic variables for abundance and richness. Also, they were reduced in the impaired sites when compared to intermediate and reference sites. The FFG ratio indicated significant differences along the impairment gradient. The FFG ratio analysis was shown to be a fast and cheap tool that can be used for monitoring aquatic ecosystems in the Atlantic For...

Revista Científica da Faculdade de Medicina de Campos

Hashimoto’s thyroiditis (HT) is an autoimmune and inflammatory disease in which antibodies are di... more Hashimoto’s thyroiditis (HT) is an autoimmune and inflammatory disease in which antibodies are directed against the thyroid gland leading to chronic inflammation and hypothyroidism. The autoimmunity against thyroid antigens can be associated to genetic background and environmental factors. Thyroid peroxidase (TPO) and thyroglobulin (TG) are the major autoantigens for characterizing the disease. HT is related to the activation of autoreactive CD4+ T cells, CD8+ cytotoxic T cells and antithyroid antibody producing-B cells. Among several cytokines related to the pathogenesis of HT, a proliferation-inducing ligand (APRIL) has been studied in the context of the establishment and/or maintenance of autoimmune diseases. The role of APRIL in the pathogenesis of HT is still poorly understood. Therefore, the present study aimed to compare APRIL serum concentration in HT patients and healthy donors by ELISA. We observed a significant decrease in APRIL concentration in HT patients when compared ...

Neuroimmunomodulation

Introduction: IL-1β, a cytokine from the innate immune response, is well known for its proinflamm... more Introduction: IL-1β, a cytokine from the innate immune response, is well known for its proinflammatory effects and stimulating activity on the hypothalamus-pituitary-adrenal axis, leading to the pituitary synthesis of adrenocorticotropic hormone followed by cortisol (and dehydroepiandrosterone – DHEA) release by the adrenal gland. While IL-1β modulates the adrenal steroidogenesis at the central level, it is unclear whether it also exerts an effect on the adrenal gland. Method: We studied the effect of IL-1β on adrenal steroid production and steroidogenic enzyme RNA expression in the human cell line NCI-H295R. We also explored eventual changes in the microRNA (miRNA) profile from IL-1β-treated NCI-H295R cells. Results: Transcripts encoding IL-1β receptors 1 and 2 were noticeable in the cell line, with cortisol and DHEA production showing a subtle increase after cytokine treatment. Transcripts from key enzymes in the steroidogenic pathway were analyzed, with no noticeable changes on t...

Medicine

Abstract Sarcoidosis is a multi-systemic granulomatous disease. Affected individuals can show spo... more Abstract Sarcoidosis is a multi-systemic granulomatous disease. Affected individuals can show spontaneous healing, develop remission with drug treatment within 2 years, or become chronically ill. Our main goal was to identify features that are related to prognosis. The study consisted of 101 patients, recruited at a single center, who were already diagnosed with sarcoidosis at the start of the study or were diagnosed within 48 months. Ninety individuals were followed-up for at least 24 months and were classified according to clinical outcome status (COS 1 to 9). Those with COS 1–4 and COS 5–9 were classified as having favorable and unfavorable outcomes, respectively. Unconditional logistic regression analyses were conducted to define which variables were associated with sarcoidosis outcomes. Subsequently, we established a scoring system to help predict the likelihood of a favorable or unfavorable outcome. Of our patients, 48% developed a chronic form of the disease (COS 5–9). Three clinical features were predictive of prognosis in sarcoidosis. We built a score-based model where the absence of rheumatological markers (1 point), normal pulmonary functions (2 points), and the presence of early respiratory symptoms manifestations (2 points) were associated with a favorable prognosis. We predicted that a patient with a score of 5 had an 86% (95% confidence interval [CI] 74%–98%) probability of having a favorable prognosis, while those with scores of 4, 3, 2, 1, and 0 had probabilities of 72% (95% CI 59–85%), 52% (95% CI 40–63%), 31% (95% CI 17–44%), 15% (95% CI 2–28%), and 7% (95% CI 0–16%) of having a favorable prognosis, respectively. Thus, our easy-to-compute algorithm can help to predict prognosis of sarcoidosis patients, facilitating their management.

BMC Infectious Diseases

Background Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwid... more Background Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwide. In some TB-HIV co-infected individuals treated for both diseases simultaneously, a pathological inflammatory reaction termed immune reconstitution inflammatory syndrome (IRIS) may occur. The risk factors for IRIS are not fully defined. We investigated the association of HLA-B, HLA-C, and KIR genotypes with TB, HIV-1 infection, and IRIS onset. Methods Patients were divided into four groups: Group 1- TB+/HIV+ (n = 88; 11 of them with IRIS), Group 2- HIV+ (n = 24), Group 3- TB+ (n = 24) and Group 4- healthy volunteers (n = 26). Patients were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. The HLA-B and HLA-C loci were typed using SBT, NGS, and KIR genes by PCR-SSP. Unconditional logistic regression models were performed for Protection/risk estimation. Results Among the individuals with TB as the outcome, KIR2DS2 was associated with increased risk for TB ons...

International Journal of Scientific Reports

Several variants involved in the expression of proteins related to immunopathological mechanisms ... more Several variants involved in the expression of proteins related to immunopathological mechanisms have been associated with dengue, but few specifically related to severe dengue. In addition, children are a group with a high incidence and mortality rate due to dengue. Several immunopathological processes developed specifically in children affected with severe dengue partially explain this risk condition. This case-control retrospective study aimed to examine the association of variants in CD209, NFKBIA, IL12B, and IL1B genes with severe dengue. These genes encode proteins involved in one of the main pathways of the immune response against dengue virus infection. The study population included affected children and householding controls from Brazil. Genotyping was performed with Real-Time TaqMan assays, and the association analysis was performed with conditional logistic regressions. We found the IL1B rs1143634 genotypes carrying the T allele to be associated with susceptibility to sev...

Journal of Epidemiology and Community Health

BackgroundThe novel coronavirus (SARS-CoV-2) is a global pandemic. The lack of protective vaccine... more BackgroundThe novel coronavirus (SARS-CoV-2) is a global pandemic. The lack of protective vaccine or treatment led most of the countries to follow the flattening of the infection curve with social isolation measures. There is evidence that socioeconomic inequalities have been shaping the COVID-19 burden among low and middle-income countries. This study described what sociodemographic and socioeconomic factors were associated with the greatest risk of COVID-19 infection and mortality and how did the importance of key neighbourhood-level socioeconomic factors change over time during the early stages of the pandemic in the Rio de Janeiro municipality, Brazil.MethodsWe linked socioeconomic attributes to confirmed cases and deaths from COVID-19 and computed age-standardised incidence and mortality rates by domains such as age, gender, crowding, education, income and race/ethnicity.ResultsThe evidence suggests that although age-standardised incidence rates were higher in wealthy neighbour...

Scientific Reports

Capsid proteins often present a positively charged arginine-rich sequence at their terminal regio... more Capsid proteins often present a positively charged arginine-rich sequence at their terminal regions, which has a fundamental role in genome packaging and particle stability for some icosahedral viruses. These sequences show little to no conservation and are structurally dynamic such that they cannot be easily detected by common sequence or structure comparisons. As a result, the occurrence and distribution of positively charged domains across the viral universe are unknown. Based on the net charge calculation of discrete protein segments, we identified proteins containing amino acid stretches with a notably high net charge (Q > + 17), which are enriched in icosahedral viruses with a distinctive bias towards arginine over lysine. We used viral particle structural data to calculate the total electrostatic charge derived from the most positively charged protein segment of capsid proteins and correlated these values with genome charges arising from the phosphates of each nucleotide. ...

PLOS Neglected Tropical Diseases

Leprosy urgently needs a precise and early diagnostic tool. The sensitivity of the direct (bacill... more Leprosy urgently needs a precise and early diagnostic tool. The sensitivity of the direct (bacilli staining, Mycobacterium leprae DNA) and indirect (antibody levels, T cell assays) diagnostics methods vary based on the clinical form. Recently, PCR-based M. leprae DNA detection has been shown to differentially diagnose leprosy from other dermatological conditions. However, accuracy can still be improved, especially for use with less invasive clinical samples. We tested different commercial DNA extraction kits: DNeasy Blood & Tissue, QIAamp DNA Microbiome, Maxwell 16 DNA Purification, PowerSoil DNA Isolation; as well as in-house phenol-chloroform and Trizol/FastPrep methods. Extraction was performed on M. leprae-infected mouse footpads and different clinical samples of leprosy patients (skin biopsies and scrapings, lesion, oral and nasal swabs, body hair, blood on FTA cards, peripheral whole blood). We observed that the Microbiome kit was able to enrich for mycobacterial DNA, most likely due the enzymatic digestion cocktail along with mechanical disruption involved in this method. Consequently, we had a significant increase in sensitivity in skin biopsies from paucibacillary leprosy patients using a duplex qPCR targeting 16S rRNA (M. leprae) and 18S rRNA (mammal) in the StepOnePlus system. Our data showed that the presence of M. leprae DNA was best detected in skin biopsies and skin scrapings, independent of the extraction method or the clinical form. For multibacillary patients, detection of M. leprae DNA in nasal swabs indicates the possibility of having a much less invasive sample that can be used for the purposes of DNA sequencing for relapse analysis and drug resistance monitoring. Overall, DNA extracted with the Microbiome kit presented the best bacilli detection rate for paucibacillary cases, indicating that investments in extraction methods with mechanical and DNA digestion should be made.

RNA Biology

ABSTRACT We investigated the gene-expression variation among humans by analysing previously publi... more ABSTRACT We investigated the gene-expression variation among humans by analysing previously published mRNA-seq and ribosome footprint profiling of heart left-ventricles from healthy donors. We ranked the genes according to their coefficient of variation values and found that the top 5% most variable genes had special features compared to the rest of the genome, such as lower mRNA levels and shorter half-lives coupled to increased translation efficiency. We observed that these genes are mostly involved with immune response and have a pleiotropic effect on disease phenotypes, indicating that asymptomatic conditions contribute to the gene expression diversity of healthy individuals.

Scientific Reports

Neutrophil extracellular traps (NETs) emerge from the cell as a DNA scaffold associated with cyto... more Neutrophil extracellular traps (NETs) emerge from the cell as a DNA scaffold associated with cytoplasmic and granular proteins, able to immobilize and kill pathogens. This association occurs following nuclear and granular membrane disintegration, allowing contact with the decondensed chromatin. Thus, it is reasonable to speculate that the DNA can also mix with miRNAs and carry them in NETs. Here, we report for the first time the presence of the miRNA carriers associated with NETs and miRNAs present in NET-enriched supernatants (NET-miRs), thus adding a novel class of molecules and new proteins that can be released and transported in the NET platform. We observed that the majority of NET-miRs were common to all four stimuli used (PMA, interleukin-8, amyloid fibrils and Leishmania), and that miRNA-142-3p carried by NETs down-modulates protein kinase Cα and regulates TNF-α production in macrophages upon NET interaction with these cells. Our findings unveil a novel role for NETs in the ...

mBio

In tuberculosis (TB), as in other infectious diseases, studies of small noncoding RNAs (sncRNA) i... more In tuberculosis (TB), as in other infectious diseases, studies of small noncoding RNAs (sncRNA) in peripheral blood have focused on microRNAs (miRNAs) but have neglected the other major sncRNA classes in spite of their potential functions in host gene regulation. Using RNA sequencing of whole blood, we have therefore determined expression of miRNA, PIWI-interacting RNA (piRNA), small nucleolar RNA (snoRNA), and small nuclear RNA (snRNA) in patients with TB (n = 8), latent TB infection (LTBI; n = 21), and treated LTBI (LTBItt; n = 6) and in uninfected exposed controls (ExC; n = 14). As expected, sncRNA reprogramming was greater in TB than in LTBI, with the greatest changes seen in miRNA populations. However, substantial dynamics were also evident in piRNA and snoRNA populations. One miRNA and 2 piRNAs were identified as moderately accurate (area under the curve [AUC] = 0.70 to 0.74) biomarkers for LTBI, as were 1 miRNA, 1 piRNA, and 2 snoRNAs (AUC = 0.79 to 0.91) for accomplished LTB...

Journal of Clinical Microbiology

Pleural tuberculosis (PlTB), a common form of extrapulmonary TB, remains as a challenge in the di... more Pleural tuberculosis (PlTB), a common form of extrapulmonary TB, remains as a challenge in the diagnosis among many causes of pleural effusion. We recently reported that the combinatorial analysis of interferon-gamma (IFN-γ), IFN-γ-inducible protein 10 (IP-10), and adenosine deaminase (ADA) from the pleural microenvironment was useful to distinguish pleural effusion caused by TB (microbiologically or not confirmed cases) among other etiologies. In this cross-sectional cohort study, a set of inflammatory mediators was quantified in blood and pleural fluid (PF) from exudative pleural effusion cases, including PlTB (n = 27) and non-PlTB (nTB; n = 25) patients. The levels of IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF, IP-10, TGF-β1, and ADA were determined using cytometric bead assay, ELISA or biochemical tests. IFN-γ, IP-10, TNF, TGF-β, and ADA quantified in PF showed significantly higher concentrations in PlTB patients when compared to nTB. When blood and PF were compared, we have id...

BMC Infectious Diseases

Background: The major factors contributing for nerve damage and permanent disabilities in leprosy... more Background: The major factors contributing for nerve damage and permanent disabilities in leprosy are type 1 or reversal reactions (RR) and type 2 or erythema nodosum leprosum (ENL). Gene profiling of leprosy reactions have shown that different pathways are activated during the course of reactions, which is consistent with the exacerbated immune response exhibited by these patients. Methods: We used qPCR to screen a panel of 90 genes related to the immune response in leprosy in RNA-derived peripheral leukocytes of patients with (N = 94) and without leprosy reactions (N = 57) in order to define expression signatures correlated to RR or ENL. Results: Our results show that there is a marked signature for RR in the blood, comprising genes mostly related to the innate immune responses, including type I IFN components, autophagy, parkins and Toll like receptors. On the other hand, only Parkin was differentially expressed in the ENL group. Conclusions: The data put together corroborates previous work that brings evidence that an acute uncontrolled exacerbated immune response designed to contain the spread of M. leprae antigens might be cause of RR pathogenesis. Identifying a blood profile useful to predict leprosy reactions prior to its development might help to reduce the morbidity associated to this disabling disease.

BackgroundHost factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Inte... more BackgroundHost factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Interferons have been reported as the main antiviral factor in Zika and other flavivirus infections.MethodsWe accessed samples from Zika pregnancies, conducted a case-control study to verify whether interferon alfa receptor 1 (IFNAR1) and interferon lambda 2 and 4 (IFNL2/4) single nucleotide polymorphisms (SNPs) contribute to CZS newborn outcome and we characterized placenta gene expression profile at term.FindingsNewborns carrying CG/CC genotypes of rs2257167 inIFNAR1presented higher risk of developing CZS (OR=3.73; IC=1.36-10.21;Pcorrected=0.02646). No association betweenIFNLSNPs and CZS was observed. Placenta from CZS cases displayed lower levels ofIFNL2andISG15along with higherIFIT5.The rs2257167 CG/CC placentas also demonstrated high levels ofIFIT5and inflammation-related genes.InterpretationWe found CZS to be related with exacerbated type I IFN and insufficient type III IFN in placenta...

BMC Genomics

Background: Citrus are among the most important crops in the world. However, there are many disea... more Background: Citrus are among the most important crops in the world. However, there are many diseases that affect Citrus caused by different pathogens. Citrus also hosts many symbiotic microorganisms in a relationship that may be advantageous for both organisms. The fungi Phyllosticta citricarpa, responsible for citrus black spot, and Phyllosticta capitalensis, an endophytic species, are examples of closely related species with different behavior in citrus. Both species are always biologically associated and are morphologically very similar, and comparing their genomes could help understanding the different lifestyles. In this study, a comparison was carried to identify genetic differences that could help us to understand the biology of P. citricarpa and P. capitalensis. Results: Drafts genomes were assembled with sizes close to 33 Mb for both fungi, carrying 15,206 and 14,797 coding sequences for P. citricarpa and P. capitalensis, respectively. Even though the functional categories of these coding sequences is similar, enrichment analysis showed that the pathogenic species presents growth and development genes that may be necessary for the pathogenicity of P. citricarpa. On the other hand, family expansion analyses showed the plasticity of the genome of these species. Particular families are expanded in the genome of an ancestor of P. capitalensis and a recent expansion can also be detected among this species. Additionally, evolution could be driven by environmental cues in P. citricarpa. Conclusions: This work demonstrated genomic differences between P. citricarpa and P. capitalensis. Although the idea that these differences could explain the different lifestyles of these fungi, we were not able to confirm this hypothesis. Genome evolution seems to be of real importance among the Phyllosticta isolates and it is leading to different biological characteristics of these species.

Journal of Cerebral Blood Flow & Metabolism

Oxidative stress and chronic inflammation in arterial walls have been implicated in intracranial ... more Oxidative stress and chronic inflammation in arterial walls have been implicated in intracranial aneurysm (IA) formation and rupture. Dimethyl fumarate (DMF) exhibits immunomodulatory properties, partly via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which reduces oxidative stress by inducing the antioxidant response element (ARE). This study evaluated the effects of DMF both in vitro, using tumor necrosis factor (TNF)-α-treated vascular smooth muscle cells (VSMC), and in vivo, using a murine elastase model to induce aneurysm formation. The mice were treated with either DMF at 100 mg/kg/day P.O. or vehicle for two weeks. DMF treatment protected VSMCs from TNF-α-induced inflammation as demonstrated by its downregulation of cytokines and upregulation of Nrf2 and smooth muscle cell markers. At higher doses, DMF also inhibited the pro-proliferative action of TNF-α by increasing apoptosis which protected the cells from aponecrosis. In mice, DMF treatment ...