RESUMO

COVID-19, caused by the SARS-COV-2 virus, induces numerous immunological reactions linked to the severity of the clinical condition of those infected. The surface Spike protein (S protein) present in Sars-CoV-2 is responsible for the infection of host cells. This protein presents a high rate of mutations, which can increase virus transmissibility, infectivity, and immune evasion. Therefore, we propose to evaluate, using immunoinformatic techniques, the predicted epitopes for the S protein of seven variants of Sars-CoV-2. MHC class I and II epitopes were predicted and further assessed for their immunogenicity, interferon-gamma (IFN-γ) inducing capacity, and antigenicity. For B cells, linear and structural epitopes were predicted. For class I MHC epitopes, 40 epitopes were found for the clades of Wuhan, Clade 2, Clade 3, and 20AEU.1, Gamma, and Delta, in addition to 38 epitopes for Alpha and 44 for Omicron. For MHC II, there were differentially predicted epitopes for all variants and eight equally predicted epitopes. These were evaluated for differences in the MHC II alleles to which they would bind. Regarding B cell epitopes, 16 were found in the Wuhan variant, 14 in 22AEU.1 and in Clade 3, 15 in Clade 2, 11 in Alpha and Delta, 13 in Gamma, and 9 in Omicron. When compared, there was a reduction in the number of predicted epitopes concerning the Spike protein, mainly in the Delta and Omicron variants. These findings corroborate the need for updates seen today in bivalent mRNA vaccines against COVID-19 to promote a targeted immune response to the main circulating variant, Omicron, leading to more robust protection against this virus and avoiding cases of reinfection. When analyzing the specific epitopes for the RBD region of the spike protein, the Omicron variant did not present a B lymphocyte epitope from position 390, whereas the epitope at position 493 for MHC was predicted only for the Alpha, Gamma, and Omicron variants.

Assuntos

COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Humanos , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/química , COVID-19/imunologia , COVID-19/virologia , COVID-19/prevenção & controle , Brasil , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/química , Epitopos/imunologia , Epitopos/química , Interferon gama/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/genética

RESUMO

Major constituents of the plant cell walls are structural proteins that belong to the hydroxyproline-rich glycoprotein (HRGP) family. Leucine-rich repeat extensin (LRX) proteins contain a leucine-rich domain and a C-terminal domain with repetitive Ser-Pro3-5 motifs that are potentially to be O-glycosylated. It has been demonstrated that pollen-specific LRX8-LRX11 from Arabidopsis thaliana are necessary to maintain the integrity of the pollen tube cell wall during polarized growth. In HRGPs, including classical extensins (EXTs), and probably in LRXs, proline residues are converted to hydroxyproline by prolyl-4-hydroxylases (P4Hs), thus defining novel O-glycosylation sites. In this context, we aimed to determine whether hydroxylation and subsequent O-glycosylation of Arabidopsis pollen LRXs are necessary for their proper function and cell wall localization in pollen tubes. We hypothesized that pollen-expressed P4H4 and P4H6 catalyze the hydroxylation of the proline units present in Ser-Pro3-5 motifs of LRX8-LRX11. Here, we show that the p4h4-1 p4h6-1 double mutant exhibits a reduction in pollen germination rates and a slight reduction in pollen tube length. Pollen germination is also inhibited by P4H inhibitors, suggesting that prolyl hydroxylation is required for pollen tube development. Plants expressing pLRX11::LRX11-GFP in the p4h4-1 p4h6-1 background show partial re-localization of LRX11-green fluorescent protein (GFP) from the pollen tube tip apoplast to the cytoplasm. Finally, immunoprecipitation-tandem mass spectrometry analysis revealed a decrease in oxidized prolines (hydroxyprolines) in LRX11-GFP in the p4h4-1 p4h6-1 background compared with lrx11 plants expressing pLRX11::LRX11-GFP. Taken together, these results suggest that P4H4 and P4H6 are required for pollen germination and for proper hydroxylation of LRX11 necessary for its localization in the cell wall of pollen tubes.

Assuntos

Proteínas de Arabidopsis , Arabidopsis , Tubo Polínico , Prolil Hidroxilases , Arabidopsis/metabolismo , Arabidopsis/genética , Hidroxilação , Tubo Polínico/crescimento & desenvolvimento , Tubo Polínico/metabolismo , Tubo Polínico/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Prolil Hidroxilases/metabolismo , Prolil Hidroxilases/genética , Parede Celular/metabolismo

RESUMO

The variability in the expression of different P-glycoprotein (P-gp) genes in parasitic nematodes of ruminants such as Haemonchus contortus (Hco-pgp) may be caused by different factors including nematode biology, geographical region and anthelmintic pressure. This study analysed the relative expression level of 10 P-gp genes in two H. contortus (Hco-pgp) field isolates from Yucatan, Mexico: 1) PARAISO (IVM-resistant) and 2) FMVZ-UADY (IVM-susceptible). These isolates were compared with a susceptible reference isolate from Puebla, Mexico, namely "CENID-SAI". In all cases H. contortus adult males were used. The Hco-pgp genes (1, 2, 3, 4, 9, 10, 11, 12, 14 and 16) were analysed for each isolate using the RT-qPCR technique. The Hco-pgp expressions were pairwise compared using the 2-ΔΔCt method and a t-test. The PARAISO isolate showed upregulation compared to the CENID-SAI isolate for Hco-pgp 1, 3, 9, 10 and 16 (P < 0.05), and the PARAISO isolate showed upregulation vs. FMVZ-UADY isolate for Hco-pgp 2 and 9 (P < 0.05), displaying 6.58- and 5.93-fold differences (P < 0.05), respectively. In contrast, similar Hco-pgp gene expression levels were recorded for FMVZ-UADY and CENID-SAI isolates except for Hco-pgp1 (P <0.1), which presented a significant upregulation (6.08-fold). The relative expression of Hco-pgp allowed confirming the IVM-resistant status of the PARAISO isolate and the IVM-susceptible status of the FMVZ-UADY isolate when compared to the CENID-SAI reference isolate. Therefore, understanding the association between the Hco-pgp genes expression of H. contortus and its IVM resistance status could help identifying the genes that could be used as molecular markers in the diagnosis of IVM resistance. However, it is important to consider the geographic origin of the nematode isolate and the deworming history at the farm of origin.

Assuntos

Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Resistência a Medicamentos , Hemoncose , Haemonchus , Ivermectina , Animais , Masculino , Anti-Helmínticos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Expressão Gênica , Hemoncose/veterinária , Hemoncose/parasitologia , Haemonchus/efeitos dos fármacos , Haemonchus/genética , Ivermectina/farmacologia , México , Fenótipo , Ovinos , Doenças dos Ovinos/parasitologia

RESUMO

Follicle-stimulating hormone (FSH) is an important protein used for bovine ovarian hyperstimulation in multiple ovulation and embryo transfer technology (MOET). Several attempts to produce bovine FSH (bFSH) in recombinant systems have been reported, nonetheless, up to date, the most commonly used products are partially purified preparations derived from porcine or ovine (pFSH or oFSH) pituitaries. Here we describe the development of a biotechnology process to produce a novel, hyperglycosylated, long-acting recombinant bFSH (LA-rbFSH) by fusing copies of a highly O-glycosylated peptide. LA-rbFSH and a nonmodified version (rbFSH) were produced in suspension CHO cell cultures and purified by IMAC with high purity levels (>99%). LA-rbFSH presented a higher glycosylation degree and sialic acid content than rbFSH. It also demonstrated a notable improvement in pharmacokinetic properties after administration to rats, including a higher concentration in plasma and a significant (seven-fold) reduction in apparent clearance (CLapp). In addition, the in vivo specific bioactivity of LA-rbFSH in rats was 2.4-fold higher compared to rbFSH. These results postulate this new molecule as an attractive substitute for commercially available porcine pituitary-derived products.

Assuntos

Cricetulus , Hormônio Foliculoestimulante , Proteínas Recombinantes , Animais , Hormônio Foliculoestimulante/metabolismo , Células CHO , Glicosilação , Bovinos , Ratos , Feminino , Biotecnologia/métodos

RESUMO

Objective: To identify the incidence of in-hospital major adverse cardiac events (MACE) with the use of mechanic thromboaspiration plus IIb/IIIa glycoprotein inhibitors versus only use of IIb/IIIa glycoprotein inhibitors on patients with acute ST elevation myocardial infarction. Method: Retrospective, observational, cohort analytic study, on patients with acute ST elevation myocardial infarction that had angiography thrombus TIMI 5 grade, treated between October 2021 and December 2022. Results: A total of 237 patients were included. In 113 patients thromboaspiration were used, 124 patients didn't used. 81.6% were men. In-hospital MACE occurred on 31.9% of patients with thromboaspiration use vs. 30.6% on patients with no use (RR: 1.05; IC95%: 0.61-1.93; p = 0.840). Incidence of malignant arrhythmias were of 8% with thromboaspiration use vs. 1.6% on patients with no use (RR: 5.27; IC95%: 1.11-24.97; p = 0.020). Conclusions: The use of thromboaspiration on concomitant treatment with IIb/IIIa glycoprotein inhibitors was similar with only IIb/IIIa glycoprotein inhibitors in reducing incidence of in-hospital MACE on patients with ST elevation acute myocardial infarction and high thrombus burden. The study has several limitations, so results should be taken with caution.

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Objetivo: Identificar la incidencia de eventos cardiovasculares adversos mayores (ECAM) intrahospitalarios con el uso de tromboaspiración mecánica más inhibidores de la glucoproteína IIb/IIIa contra solo inhibidores de la glucoproteína IIb/IIIa en pacientes con infarto agudo al miocardio con elevación del segmento ST (IAMCEST). Método: Estudio retrospectivo, observacional, analítico, de cohorte, en pacientes con IAMCEST con trombo angiográfico de grado TIMI 5, tratados entre octubre de 2021 y diciembre de 2022. Resultados: Cumplieron los criterios de inclusión 237 pacientes. En 113 se usó tromboaspirador más inhibidores IIb/IIIa y en 124 solo inhibidores IIb/IIIa. El 81.6% fueron hombres. La incidencia de ECAM intrahospitalarios fue del 31.9% en los pacientes con tromboaspiración y del 30.6% en los pacientes con solo inhibidores IIb/IIIa (RR: 1.05; IC95%: 0.61-1.93; p = 0.840). La incidencia de arritmias graves fue del 8% en los pacientes con tromboaspiración y del 1.6% en los pacientes con solo inhibidores IIb/IIIa (RR: 5.27; IC95%: 1.11-24.97; p = 0.020). Conclusiones: La frecuencia de ECAM asociados al uso de tromboaspiración mecánica como coadyuvante a los inhibidores de la glucoproteína IIb/IIIa en pacientes con IAMCEST y trombo angiográfico de grado TIMI 5 no es diferente de la de aquellos pacientes en las que solo se utilizan inhibidores de la glucoproteína IIb/IIa. El estudio tiene varias limitaciones, por lo que los resultados deben tomarse con cautela.

RESUMO

The worldwide spread of SARS-CoV-2 has led to a significant economic and social burden on a global scale. Even though the pandemic has concluded, apprehension remains regarding the emergence of highly transmissible variants capable of evading immunity induced by either vaccination or prior infection. The success of viral penetration is due to the specific amino acid residues of the receptor-binding motif (RBM) involved in viral attachment. This region interacts with the cellular receptor ACE2, triggering a neutralizing antibody (nAb) response. In this study, we evaluated serum immunogenicity from individuals who received either a single dose or a combination of different vaccines against the original SARS-CoV-2 strain and a mutated linear RBM. Despite a modest antibody response to wild-type SARS-CoV-2 RBM, the Omicron variants exhibit four mutations in the RBM (S477N, T478K, E484A, and F486V) that result in even lower antibody titers. The primary immune responses observed were directed toward IgA and IgG. While nAbs typically target the RBD, our investigation has unveiled reduced seroreactivity within the RBD's crucial subregion, the RBM. This deficiency may have implications for the generation of protective nAbs. An evaluation of S1WT and S2WT RBM peptides binding to nAbs using microscale thermophoresis revealed a higher affinity (35 nM) for the S2WT sequence (GSTPCNGVEGFNCYF), which includes the FNCY patch. Our findings suggest that the linear RBM of SARS-CoV-2 is not an immunodominant region in vaccinated individuals. Comprehending the intricate dynamics of the humoral response, its interplay with viral evolution, and host genetics is crucial for formulating effective vaccination strategies, targeting not only SARS-CoV-2 but also anticipating potential future coronaviruses.

RESUMO

To date, limited information is available on cytomegalovirus (CMV) and lymphocryptovirus (LCV) from Chlorocebus monkeys. We report here high detection rates of herpesviruses in free-roaming African green monkeys (AGMs, Chlorocebus sabaeus) (26.4%, 23/87) and in captive AGMs (75%, 3/4) with respiratory disease on the Caribbean Island of St. Kitts. LCV (81.25%) was more prevalent than CMV (18.75%) in the AGMs. Applying a bigenic PCR approach (targeting DNA polymerase (DPOL) and glycoprotein B (gB) genes), long sequences were obtained from representative AGM CMV (KNA-SD6) and LCV (KNA-E4, -N6 and -R15) samples, and mixed LCV infections were identified in KNA-N6 and -R15. The nucleotide (nt) sequence (partial DPOL-intergenic region-partial gB) and partial DPOL- and gB-amino acid (aa) sequences of AGM CMV KNA-SD6 were closely related to Cytomegalovirus cercopithecinebeta5 isolates from grivet monkeys, whilst those of AGM LCV KNA-E4 and -N6 (and E4-like gB of KNA-R15) were more closely related to cognate sequences of erythrocebus patas LCV1 from patas monkey than other LCVs, corroborating the concept of cospeciation in the evolution of CMV/LCV. On the other hand, the partial DPOL aa sequence of KNA-R15, and additional gB sequences (N6-gB-2 and R15-gB-2) from samples KNA-N6 and -R15 (respectively) appeared to be distinct from those of Old World monkey LCVs, indicating LCV evolutionary patterns that were not synchronous with those of host species. The present study is the first to report the molecular prevalence and genetic diversity of CMV/LCV from free-roaming/wild and captive AGMs, and is the first report on analysis of CMV nt/deduced aa sequences from AGMs and LCV gB sequences from Chlorocebus monkeys.

Assuntos

Infecções por Citomegalovirus , Lymphocryptovirus , Animais , Chlorocebus aethiops , Lymphocryptovirus/genética , Citomegalovirus/genética , Filogenia , Herpesvirus Humano 4 , Glicoproteínas/genética , Variação Genética

RESUMO

Orosomucoid, or alpha-1 acid glycoprotein (AGP), is a major acute-phase protein expressed in response to systemic injury and inflammation. AGP has been described as an inhibitor of neutrophil migration on sepsis, particularly its immunomodulation effects. AGP's biological functions in coronavirus disease 2019 (COVID-19) are not understood. We sought to investigate the role of AGP in severe COVID-19 infection patients and neutrophils infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Epidemiological data, AGP levels, and other laboratory parameters were measured in blood samples from 56 subjects hospitalized in the ICU with SARS-CoV-2 infection. To evaluate the role of AGP in NETosis in neutrophils, blood samples from health patients were collected, and neutrophils were separated and infected with SARS-CoV-2. Those neutrophils were treated with AGP or vehicle, and NETosis was analyzed by flow cytometry. AGP was upregulated in severe COVID-19 patients (p<0.05). AGP level was positively correlated with IL-6 and C-reactive protein (respectively, p=0.005, p=0.002) and negatively correlated with lactate (p=0.004). AGP treatment downregulated early and late NETosis (respectively, 35.7% and 43.5%) in neutrophils infected with SARS-CoV-2 and up-regulated IL-6 supernatant culture expression (p<0.0001). Our data showed increased AGP in COVID-19 infection and contributed to NETosis regulation and increased IL-6 production, possibly related to the Cytokine storm in COVID-19.

Assuntos

COVID-19 , Humanos , COVID-19/metabolismo , Neutrófilos/metabolismo , Orosomucoide/metabolismo , Orosomucoide/farmacologia , SARS-CoV-2 , Interleucina-6/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Imunoproteínas/metabolismo

RESUMO

BACKGROUND: The current challenge in clinical cancer treatment is chemoresistance. Colon cells have inherently higher xenobiotic transporters expression and hence can attain resistance rapidly. Increased levels of TGF-ß2 expression in patients have been attributed to cancer progression, aggressiveness, and resistance. To investigate resistance progression, we treated doxorubicin (dox) to HT-29 colon adenocarcinoma cells in the presence or absence of TGF-ß2 ligand. METHODS: After 1, 3-, and 7-day treatment, we investigated cell proliferation, viability, and cytotoxicity by MTT, trypan blue staining, and lactate dehydrogenase enzyme release. The mechanism of cell death was elucidated by hoechst33342 and propidium iodide dual staining and apoptosis assay. The development of resistance was detected by rhodamine123 efflux and P-glycoprotein (P-gp)/MDR1 antibody staining through fluorimetry and flow cytometry. The colony formation ability of the cells was also elucidated. RESULTS: Inhibition of cell proliferation was noted after day 1, while a significant reduction in viability and a significant increase in lactate dehydrogenase release was detected after day 3. Reduction of intracellular rhodamine123 levels was detected after day 3 and was significantly lower in dox with TGF-ß2 treatment compared to dox alone. Increased surface P-gp levels after days 3 and 7 were observed in the treated groups. Hoechst33342/propidium iodide staining and apoptosis assay indicated non-apoptotic cell death. The cells treated with TGF-ß2 had higher colony formation ability. CONCLUSIONS: TGF-ß2 expression might play a significant role in the development of chemoresistance to doxorubicin in Duke's type B colon adenocarcinoma cell line, HT-29.

Assuntos

Adenocarcinoma , Antibióticos Antineoplásicos , Apoptose , Proliferação de Células , Neoplasias do Colo , Doxorrubicina , Resistencia a Medicamentos Antineoplásicos , Fator de Crescimento Transformador beta2 , Humanos , Doxorrubicina/farmacologia , Adenocarcinoma/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Neoplasias do Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Antibióticos Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Células HT29 , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos

RESUMO

Ebola virus disease (EVD) causes outbreaks and epidemics in West Africa that persist until today. The envelope glycoprotein of Ebola virus (GP) consists of two subunits, GP1 and GP2, and plays a key role in anchoring or fusing the virus to the host cell in its active form on the virion surface. Toremifene (TOR) is a ligand that mainly acts as an estrogen receptor antagonist; however, a recent study showed a strong and efficient interaction with GP. In this context, we aimed to evaluate the energetic affinity features involved in the interaction between GP and toremifene by computer simulation techniques using the Molecular Fractionation Method with Conjugate Caps (MFCC) scheme and quantum-mechanical (QM) calculations, as well as missense mutations to assess protein stability. We identified ASP522, GLU100, TYR517, THR519, LEU186, LEU515 as the most attractive residues in the EBOV glycoprotein structure that form the binding pocket. We divided toremifene into three regions and evaluated that region i was more important than region iii and region ii for the formation of the TOR-GP1/GP2 complex, which might control the molecular remodeling process of TOR. The mutations that caused more destabilization were ARG134, LEU515, TYR517 and ARG559, while those that caused stabilization were GLU523 and ASP522. TYR517 is a critical residue for the binding of TOR, and is highly conserved among EBOV species. Our results may help to elucidate the mechanism of drug action on the GP protein of the Ebola virus and subsequently develop new pharmacological approaches against EVD.Communicated by Ramaswamy H. Sarma.

RESUMO

Saint Louis encephalitis virus (SLEV) infection is an arbovirosis associated with a broad spectrum of neurological complications. We present a case of a 55-year-old man hailing from Manaus, a city situated in the heart of the Amazon Rainforest, who exhibited symptoms of vertigo, tremors, urinary and fecal retention, compromised gait, and encephalopathy 3 weeks following SLEV infection. Neuroaxis MRI revealed diffuse, asymmetric, and poorly defined margins hyperintense lesions with peripheral and ring enhancement in subcortical white matter, as well as severe spinal cord involvement. Serology for SLEV was positive both on serum and cerebrospinal fluid. To the best of our knowledge, the present report is the first to show brain lesions along with myelitis as a post-infectious complication of SLEV infection.

Assuntos

Encefalite de St. Louis , Encefalomielite Aguda Disseminada , Masculino , Humanos , Pessoa de Meia-Idade , Vírus da Encefalite de St. Louis/fisiologia , Encefalomielite Aguda Disseminada/diagnóstico por imagem , Encefalomielite Aguda Disseminada/etiologia , Encefalite de St. Louis/complicações , Encefalite de St. Louis/diagnóstico

RESUMO

SARS-CoV-2 genome underwent mutations since it started circulating within the human population. The aim of this study was to understand the fluctuation of the spike clusters concomitant to the population immunity either due to natural infection and/or vaccination in a state of Brazil that had both high rate of natural infection and vaccination coverage. A total of 1725 SARS-CoV-2 sequences from the state of Rio Grande do Norte, Brazil, were retrieved from GISAID and subjected to cluster analysis. Immunoinformatics were used to predict T- and B-cell epitopes, followed by simulation to estimate either pro- or anti-inflammatory responses and to correlate with circulating variants. From March 2020 to June 2022, the state of Rio Grande do Norte reported 579,931 COVID-19 cases with a 1.4% fatality rate across the three major waves: May-Sept 2020, Feb-Aug 2021, and Jan-Mar 2022. Cluster 0 variants (wild type strain, Zeta) were prevalent in the first wave and Delta (AY.*), which circulated in Brazil in the latter half of 2021, featuring fewer unique epitopes. Cluster 1 (Gamma (P.1 + P.1.*)) dominated the first half of 2021. Late 2021 had two new clusters, Cluster 2 (Omicron, (B.1.1.529 + BA.*)), and Cluster 3 (BA.*) with the most unique epitopes, in addition to Cluster 4 (Delta sub lineages) which emerged in the second half of 2021 with fewer unique epitopes. Cluster 1 epitopes showed a high pro-inflammatory propensity, while others exhibited a balanced cytokine induction. The clustering method effectively identified Spike groups that may contribute to immune evasion and clinical presentation, and explain in part the clinical outcome.

Assuntos

COVID-19 , Humanos , Brasil/epidemiologia , COVID-19/epidemiologia , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Epitopos de Linfócito B , Glicoproteínas

RESUMO

OBJECTIVES: Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients. METHODS: In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage. RESULTS: Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio [OR] 1.82; 95% CI 1.05, 3.15; adjusted P = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P = 0.007), aß2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P < 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P = 0.016). CONCLUSIONS: DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden.

Assuntos

Síndrome Antifosfolipídica , Hiperlipidemias , Humanos , Síndrome Antifosfolipídica/complicações , Estudos Transversais , Sistema de Registros , Anticorpos Antifosfolipídeos

RESUMO

The Leishmaniinae subfamily of the Trypanosomatidae contains both genus Zelonia (monoxenous) and Endotrypanum (dixenous). They are amongst the nearest known relatives of Leishmania, which comprises many human pathogens widespread in the developing world. These closely related lineages are models for the genomic biology of monoxenous and dixenous parasites. Herein, we used comparative genomics to identify the orthologous groups (OGs) shared among 26 Leishmaniinae species to investigate gene family expansion/contraction and applied two phylogenomic approaches to confirm relationships within the subfamily. The Endotrypanum monterogeii and Zelonia costaricensis genomes were assembled, with sizes of 29.9 Mb and 38.0 Mb and 9.711 and 12.201 predicted protein-coding genes, respectively. The genome of E. monterogeii displayed a higher number of multicopy cell surface protein families, including glycoprotein 63 and glycoprotein 46, compared to Leishmania spp. The genome of Z. costaricensis presents expansions of BT1 and amino acid transporters and proteins containing leucine-rich repeat domains, as well as a loss of ABC-type transporters. In total, 415 and 85 lineage-specific OGs were identified in Z. costaricensis and E. monterogeii. The evolutionary relationships within the subfamily were confirmed using the supermatrix (3384 protein-coding genes) and supertree methods. Overall, this study showed new expansions of multigene families in monoxenous and dixenous parasites of the subfamily Leishmaniinae.

RESUMO

Introducción: La enfermedad asociada a anticuerpos contra la glicoproteína de mielina del oligodendrocito (MOGAD, por sus siglas en inglés) es una entidad clínica recientemente identificada. La frecuencia de presentación del MOGAD es desconocida, pero se considera baja con respecto a otras enfermedades inflamatorias desmielinizantes. Materiales y métodos: Revisión narrativa de la literatura. Resultados: Las manifestaciones clínicas de esta condición son heterogéneas e incluyen neuritis óptica, mielitis, desmielinización multifocal del sistema nervioso central y encefalitis cortical. Se han descrito algunos hallazgos radiológicos que aumentan la sospecha diagnóstica, como el realce perineural del nervio óptico, el signo de la H en el cordón espinal y la resolución de lesiones T2 con el tiempo. El diagnóstico se basa en la detección de inmunoglobulinas G específicas contra MOG, en el contexto clínico adecuado. El tratamiento consiste en manejo de los ataques agudos con dosis altas de corticoides y en algunos casos se deberá considerar la inmunosupresión crónica, considerar la inmunosupresión crónica en pacientes con recurrencia o con discapacidad severa residual tras el primer evento. Conclusiones: En esta revisión narrativa se resumen los aspectos clave con respecto a la fisiopatología, las manifestaciones, el diagnóstico y el tratamiento de la MOGAD.

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Introduction: The disease associated with antibodies against the myelin oligodendrocyte glycoprotein (MOGAD) is a recently identified clinical entity, with unknown frequency, but is considered low compared to other demyelinating inflammatory diseases. Materials And Methods: Narrative review. Results: The clinical manifestations are heterogeneous, ranging from optic neuritis or myelitis to multi-focal CNS demyelination or cortical encephalitis. There have been described characteristic MRI features that increase the diagnostic suspicion, such as perineural optic nerve enhancement, spinal cord H-sign or T2-lesion resolution over time. The diagnosis is based on the detection of specific G- immunoglobulins against MOG, in the suggestive clinical context. Acute treatment is based on high dose steroids and maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the first attack. Conclusions: In this narrative review, fundamental aspects of pathophysiology, clinical and radiological manifestations, diagnosis and treatment of MOGAD are discussed.

Assuntos

Neurite Óptica , Glicoproteína Oligodendrócito-Mielina , Mielite , Sorologia , Imageamento por Ressonância Magnética , Terapia de Imunossupressão

RESUMO

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory disorder of the CNS with a variety of clinical manifestations, including cerebral edema. Case Summary: A 7-year-old boy presented with headaches, nausea, and somnolence. He was found to have cerebral edema that progressed to brainstem herniation. Invasive multimodality neuromonitoring was initiated to guide management of intracranial hypertension and cerebral hypoxia while he received empiric therapies for neuroinflammation. Workup revealed serum myelin oligodendrocyte glycoprotein antibodies. He survived with a favorable neurologic outcome. Conclusion: We describe a child who presented with cerebral edema and was ultimately diagnosed with MOGAD. Much of his management was guided using data from invasive multimodality neuromonitoring. Invasive multimodality neuromonitoring may have utility in managing life-threatening cerebral edema due to neuroinflammation.

RESUMO

Genetic characterizations of rabies viruses circulating in carnivore and non-carnivore animals were investigated for the first time in Arkhangai province, a central region of Mongolia. Also, glycoprotein gene of the rabies virus was sequenced for the first time in Mongolia. The nucleotide sequences of the glycoprotein and nucleoprotein genes were analysed, revealing the presence of multiple lineages in this area. Of particular concern are the lineages identified in carnivores, which might emerge to spread throughout Mongolia, further facilitating transboundary transmission to neighbouring countries, including China and Russia.

Assuntos

Vírus da Raiva , Raiva , Animais , Vírus da Raiva/genética , Raiva/epidemiologia , Raiva/veterinária , Nucleoproteínas/genética , Mongólia , Filogenia

RESUMO

Abstract Background Anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibody-associated disease (MOGAD) is an immune-mediated neurological disorder with a broad spectrum of clinical presentation that is often difficult to distinguish from other demyelinating diseases, such as multiple sclerosis and neuromyelitis optica spectrum disorder. Objective To describe the clinical and paraclinical characteristics of MOGAD in a Brazilian tertiary center. Methods We retrospectively reviewed the records of adult and pediatric patients who tested positive for anti-MOG antibodies and presented with clinical and radiological diseases compatible with MOGAD. Results Forty-one patients (10 children) were included: 56% female, 58% Caucasian, mean age at onset 31 years (range 6-64), with a mean disease duration of 59.6 months (range 1-264 months). The most frequent onset presentation was optic neuritis (68%), acute disseminated encephalomyelitis (ADEM, 12%), and myelitis (10%). A monophasic disease course was observed in 49%. EDSS median was 2.1 at the last visit. Most patients (83%) were under continuous immunosuppressive treatment. Azathioprine was the first-line treatment in 59%. In all ADEM cases, conus, and root involvement was radiologically observed on MRI. Conclusion Brazilian MOGAD patients presented with a similar spectrum of previously reported MOGAD phenotypes. Conus and spinal root involvement seems to be frequently present in MOGAD-ADEM and could serve as radiologic characteristics of this clinical entity.

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Resumo Antecedentes A doença associada ao anticorpo da glicoproteína da mielina de oligodendrócitos (anti-MOG; MOGAD) é uma doença neurológica imunomediada com um amplo espectro de apresentações clínicas que muitas vezes é difícil de distinguir de outras doenças desmielinizantes, como a esclerose múltipla e o distúrbio do espectro da neuromielite óptica. Objetivo Descrever as características clínicas e paraclínicas da MOGAD em um centro terciário brasileiro. Métodos Revisamos retrospectivamente os prontuários dos pacientes adultos e pediátricos que testaram positivos para anticorpos anti-MOG e apresentaram um quadro clínico e radiológico compatível com MOGAD. Resultados Quarenta e um pacientes (10 crianças) foram incluídos: 56% do sexo feminino, 58% caucasianos, idade média de início da doença foi 31 anos (intervalo de 6-64), com duração média da doença de 59,6 meses (intervalo de 1-264 meses). A apresentação inicial mais frequente foi neurite óptica (68%), seguida pela encefalomielite disseminada aguda (ADEM, 12%) e mielite (10%). Um curso monofásico da doença foi observado em 49%. EDSS foi de 2,1 na última visita. A maioria dos pacientes (83%) estava sob tratamento imunossupressor contínuo. Azatioprina foi o tratamento de primeira linha em 59%. Em todos os casos de ADEM, o envolvimento do cone medular e das raízes espinhais foi observado radiologicamente na ressonância magnética. Conclusão Os pacientes brasileiros com MOGAD apresentam um espectro clínico e radiológico semelhante aos fenótipos de MOGAD relatados anteriormente. O envolvimento do cone e das raízes espinhais parece estar frequentemente presente no MOGAD-ADEM e poderia servir como característica radiológica nesta entidade.

RESUMO

Cancer multidrug resistance (MDR) is one of the main mechanisms contributing to therapy failure and mortality. Overexpression of drug transporters of the ABC family (ATP-binding cassette) is a major cause of MDR. Extracellular vesicles (EVs) are nanoparticles released by most cells of the organism involved in cell-cell communication. Their cargo mainly comprises, proteins, nucleic acids, and lipids, which are transferred from a donor cell to a target cell and lead to phenotypical changes. In this article, we review the scientific evidence addressing the regulation of ABC transporters by EV-mediated cell-cell communication. MDR transfer from drug-resistant to drug-sensitive cells has been identified in several tumor entities. This was attributed, in some cases, to the direct shuttle of transporter molecules or its coding mRNA between cells. Also, EV-mediated transport of regulatory proteins (e.g., transcription factors) and noncoding RNAs have been indicated to induce MDR. Conversely, the transfer of a drug-sensitive phenotype via EVs has also been reported. Additionally, interactions between non-tumor cells and the tumor cells with an impact on MDR are presented. Finally, we highlight uninvestigated aspects and possible approaches to exploiting this knowledge toward the identification of druggable processes and molecules and, ultimately, the development of novel therapeutic strategies.

RESUMO

Bovine viral diarrhea virus (BVDV) is considered the most important viral pathogen in ruminants worldwide due to the broad range of clinical manifestations displayed by infected animals. Therefore, infection with BVDV leads to severe economic losses in several countries' beef and dairy industries. Vaccination prevents reproductive failure and gastrointestinal and respiratory disorders caused by BVDV infection. However, considering their limitations, conventional vaccines such as live, attenuated, and killed viruses have been applied. Hence, different studies have described subunit vaccines as an effective and safe alternative for BVDV protection. Therefore, in this study, the ectodomain of E2 (E2e) glycoprotein from NADL BVDV strain was expressed in mammalian cells and used in two vaccine formulations to evaluate immunogenicity and protection against BVDV conferred in a murine model. Formulations consisted of solo E2e glycoprotein and E2e glycoprotein emulsified in adjuvant ISA 61 VG. Five groups of 6 mice of 6-to-8-week-old were immunized thrice on days 1, 15, and 30 by intraperitoneal injection with the mentioned formulations and controls. To evaluate the conferred protection against BVDV, mice were challenged six weeks after the third immunization. In addition, the humoral immune response was evaluated after vaccination and challenge. Mice groups inoculated with solo E2e and the E2e + ISA 61 VG displayed neutralizing titers; however, the E2 antibody titers in the E2e + ISA 61 VG group were significantly higher than the mice group immunized with the solo E2e glycoprotein. In addition, immunization using E2e + ISA 61 VG prevents animals from developing severe lesions in surveyed tissues. Moreover, this group acquired protection against the BVDV challenge, evidenced by a significant reduction of positive staining for BVDV antigen in the lungs, liver, and brain between the experimental groups. Our findings demonstrated that using E2e + ISA 61 VG induces greater BVDV protection by an early humoral response and reduced histopathological lesions and BVDV antigen detection in affected organs, indicating that E2e + ISA 61 VG subunit formulation can be considered as a putative vaccine candidate against BVDV. The efficacy and safety of this vaccine candidate in cattle requires further investigation.