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1.
Nat Immunol ; 25(9): 1692-1703, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39080486

RESUMO

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn's disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome-ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome-ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention.


Assuntos
Doença de Crohn , Imunoglobulina G , Manose , Polissacarídeos , Doença de Crohn/imunologia , Doença de Crohn/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Animais , Humanos , Glicosilação , Manose/metabolismo , Manose/imunologia , Camundongos , Polissacarídeos/imunologia , Polissacarídeos/metabolismo , Feminino , Saccharomyces cerevisiae/imunologia , Masculino , Adulto , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Biomarcadores/sangue , Pessoa de Meia-Idade , Fragmentos Fc das Imunoglobulinas/imunologia , Glicoproteínas
2.
PLoS Genet ; 20(7): e1011181, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39074150

RESUMO

When replication forks encounter damaged DNA, cells utilize damage tolerance mechanisms to allow replication to proceed. These include translesion synthesis at the fork, postreplication gap filling, and template switching via fork reversal or homologous recombination. The extent to which these different damage tolerance mechanisms are utilized depends on cell, tissue, and developmental context-specific cues, the last two of which are poorly understood. To address this gap, we have investigated damage tolerance responses in Drosophila melanogaster. We report that tolerance of DNA alkylation damage in rapidly dividing larval tissues depends heavily on translesion synthesis. Furthermore, we show that the REV1 protein plays a multi-faceted role in damage tolerance in Drosophila. Larvae lacking REV1 are hypersensitive to methyl methanesulfonate (MMS) and have highly elevated levels of γ-H2Av (Drosophila γ-H2AX) foci and chromosome aberrations in MMS-treated tissues. Loss of the REV1 C-terminal domain (CTD), which recruits multiple translesion polymerases to damage sites, sensitizes flies to MMS. In the absence of the REV1 CTD, DNA polymerases eta and zeta become critical for MMS tolerance. In addition, flies lacking REV3, the catalytic subunit of polymerase zeta, require the deoxycytidyl transferase activity of REV1 to tolerate MMS. Together, our results demonstrate that Drosophila prioritize the use of multiple translesion polymerases to tolerate alkylation damage and highlight the critical role of REV1 in the coordination of this response to prevent genome instability.


Assuntos
Dano ao DNA , Reparo do DNA , Replicação do DNA , DNA Polimerase Dirigida por DNA , Proteínas de Drosophila , Drosophila melanogaster , Metanossulfonato de Metila , Nucleotidiltransferases , Animais , Drosophila melanogaster/genética , DNA Polimerase Dirigida por DNA/metabolismo , DNA Polimerase Dirigida por DNA/genética , Metanossulfonato de Metila/farmacologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Alquilação , Reparo do DNA/genética , Replicação do DNA/genética , Larva/genética , Histonas/metabolismo , Histonas/genética
3.
N Engl J Med ; 388(6): 518-528, 2023 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-36780676

RESUMO

BACKGROUND: The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 µg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization. RESULTS: A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19-related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.).


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Interferon lambda , Adulto , Humanos , Teorema de Bayes , COVID-19/terapia , Método Duplo-Cego , Interferon lambda/administração & dosagem , Interferon lambda/efeitos adversos , Interferon lambda/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , SARS-CoV-2 , Resultado do Tratamento , Assistência Ambulatorial , Injeções Subcutâneas , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Vacinas contra COVID-19/uso terapêutico , Vacinação
4.
J Proteome Res ; 2024 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-39475502

RESUMO

Pharmacological targeting of metabolic pathways represents an appealing strategy to selectively kill cancer cells while promoting antitumor functions of stromal cells. In this study, we assessed the effectiveness of 13 metabolic drugs (MDs) in steering in vitro generated breast tumor-educated macrophages (TEMs) toward an antitumoral phenotype. For that, the production of vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF-α), two important regulators of tumor progression, was evaluated. Notably, dichloroacetate (DCA), 6-aminonicotinamide (6-AN), and etomoxir decreased VEGF production and enhanced TNF-α release. Hence, we further clarified their impact on TEM metabolism using an untargeted NMR-based metabolomics approach. DCA downregulated glycolysis and enhanced the utilization of extracellular substrates like lactate while reconfiguring lipid metabolism. Several DCA-induced changes significantly correlated with heightened TNF-α production in response to pro-inflammatory stimulation. The inhibition of the pentose phosphate pathway by 6-AN was accompanied by enhanced glutaminolysis, which correlated with a decreased level of VEGF production. In etomoxir-treated TEM, inhibition of fatty acid oxidation was compensated through upregulation of glycolysis, catabolism of intracellular amino acids, and consumption of extracellular branched chain alpha-ketoacids (BCKA) and citrate. Overall, our results offer a comprehensive view of the metabolic signature of each MD in breast TEM and highlight putative correlations with phenotypic effects.

5.
Small ; 20(27): e2303421, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38533978

RESUMO

Materials with tunable negative electromagnetic performance, i.e., where dielectric permittivity becomes negative, have long been pursued in materials research due to their peculiar electromagnetic (EM) characteristics. Here, this promising feature is reported in materials on the case of plasma-synthesized nitrogen-doped graphene sheets with tunable permittivity over a wide (1-40 GHz) frequency range. Selectively incorporated nitrogen atoms in a graphene scaffold tailor the electronic structure in a way that provides an ultra-low energy (0.5-2 eV) 2D surface plasmon excitation, leading to subunitary and negative dielectric constant values in the Ka-band, from 30 up to 40 GHz. By allowing the tailoring of structures at atomic scale, this novel plasma-based approach creates a new paradigm for designing 2D nanomaterials like nanocarbons with controllable and tunable permittivity, opening a path to the next generation of 2D metamaterials.

6.
Brain Behav Immun ; 119: 333-350, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38561095

RESUMO

Neonatal sepsis remains one of the leading causes of mortality in newborns. Several brainstem-regulated physiological processes undergo disruption during neonatal sepsis. Mechanistic knowledge gaps exist at the interplay between metabolism and immune activation to brainstem neural circuits and pertinent physiological functions in neonates. To delineate this association, we induced systemic inflammation either by TLR4 (LPS) or TLR1/2 (PAM3CSK4) ligand administration in postnatal day 5 mice (PD5). Our findings show that LPS and PAM3CSK4 evoke substantial changes in respiration and metabolism. Physiological trade-offs led to hypometabolic-hypothermic responses due to LPS, but not PAM3CSK4, whereas to both TLR ligands blunted respiratory chemoreflexes. Neuroinflammatory pathways modulation in brainstem showed more robust effects in LPS than PAM3CSK4. Brainstem neurons, microglia, and astrocyte gene expression analyses showed unique responses to TLR ligands. PAM3CSK4 did not significantly modulate gene expression changes in GLAST-1 positive brainstem astrocytes. PD5 pups receiving PAM3CSK4 failed to maintain a prolonged metabolic state repression, which correlated to enhanced gasping latency and impaired autoresuscitation during anoxic chemoreflex challenges. In contrast, LPS administered pups showed no significant changes in anoxic chemoreflex. Electrophysiological studies from brainstem slices prepared from pups exposed to either TLR4 or PAM3CSK4 showed compromised transmission between preBötzinger complex and Hypoglossal as an exclusive response to the TLR1/2 ligand. Spatial gene expression analysis demonstrated a region-specific modulation of PAM3CSK4 within the raphe nucleus relative to other anatomical sites evaluated. Our findings suggest that metabolic changes due to inflammation might be a crucial tolerance mechanism for neonatal sepsis preserving neural control of breathing.


Assuntos
Animais Recém-Nascidos , Tronco Encefálico , Lipopolissacarídeos , Sepse Neonatal , Receptor 1 Toll-Like , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Animais , Camundongos , Receptor 4 Toll-Like/metabolismo , Lipopolissacarídeos/farmacologia , Receptor 2 Toll-Like/metabolismo , Sepse Neonatal/metabolismo , Tronco Encefálico/metabolismo , Receptor 1 Toll-Like/metabolismo , Lipopeptídeos/farmacologia , Respiração/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Astrócitos/metabolismo , Masculino , Ligantes , Microglia/metabolismo , Feminino , Inflamação/metabolismo
7.
Eur J Clin Microbiol Infect Dis ; 43(3): 605-610, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38112967

RESUMO

FASTinov® developed a rapid antimicrobial susceptibility test that includes the purification of a bacterial suspension directly from positive blood cultures (BC). In order to streamline laboratory workflow, the use of the bacterial suspension obtained through FASTinov® sample prep was tested for identification (ID) by matrix absorption laser deionization-time of flight mass spectrometry (MALDI-TOF MS) (Bruker) in 364 positive BC, and its accuracy assessed comparing with the MALDI-TOF MS ID of the next-day subcultured colonies. FASTinov sample prep was highly reliable for rapid ID directly from BC with proportion of agreement of 94.9% for Gram-positive and 96.3% for Gram-negative bacteria.


Assuntos
Bacteriemia , Hemocultura , Humanos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Bactérias , Bactérias Gram-Negativas , Laboratórios , Bacteriemia/microbiologia
8.
Nature ; 624(7992): 530-531, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38123802
9.
Adv Exp Med Biol ; 1443: 173-186, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38409421

RESUMO

Kidney disease is a critical and potentially life-threatening degenerative condition that poses a significant global public health challenge due to its elevated rates of morbidity and mortality. It manifests primarily in two distinct clinical forms: acute kidney injury (AKI) and chronic kidney disease (CKD). The development of these conditions hinges on a multitude of factors, including the etiological agents and the presence of coexisting medical conditions. Despite disparities in their underlying pathogenic mechanisms, both AKI and CKD can progress to end-stage kidney disease (ESKD). This advanced stage is characterized by organ failure and its associated complications, greatly increasing the risk of mortality. There is an urgent need to delve into the pathogenic mechanisms underlying these diseases and to identify novel biomarkers that can facilitate earlier diagnosis. Such early detection is crucial for enhancing the efficacy of therapy and impeding disease progression. In this context, proteomic approaches have emerged as invaluable tools for uncovering potential new markers of different pathological conditions, including kidney diseases. In this chapter, we overview the recent discoveries achieved through diverse proteomic techniques aimed at identifying novel molecules that may play a pivotal role in kidney diseases such as diabetic kidney disease (DKD), IgA nephropathy (IgAN), CKD of unknown origin (CKDu), autosomal dominant polycystic kidney disease (ADPKD), lupus nephritis (LN), hypertensive nephropathy (HN), and COVID-19-associated acute kidney injury (COVID-AKI).


Assuntos
Injúria Renal Aguda , Falência Renal Crônica , Insuficiência Renal Crônica , Humanos , Proteômica/métodos , Injúria Renal Aguda/diagnóstico , Diagnóstico Precoce , Biomarcadores
10.
Chem Biodivers ; : e202401406, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39103292

RESUMO

Toxicological studies are important to investigate the genotoxic effects of various substances. Allium cepa can be used as test model for this purpose. This review summarizes the scope and applications for this A. cepa test model. For this, an up-to-date (April 2023) literature search was made in the Science Direct, PubMed, and Web of Science databases to find published evidence on studies performed using A. cepa as a test model. Out of 3,748 studies, 74 fit the inclusion criteria. The results showed that the use of the test model A. cepa contributed considerably to measuring the toxicological potential of plant extracts, proving the efficacy of the test as a potent bioindicator of toxic effects. In addition, 27 studies used more than one test system to verify the toxicological potential of extracts and fractions. Studies have shown that the A. cepa model has the potential to replace other test systems that make use of animals and cell cultures, besides having other advantages such as low cost, ease of execution, and good conditions for the observation of chromosomes. In conclusion, the A. cepa test can be considered one of the potential biomonitoring systems in toxicological studies of crude extracts.

11.
Int J Mol Sci ; 25(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38474134

RESUMO

The slmap gene is alternatively spliced to generate many isoforms that are abundant in developing myocardium. The largest protein isoform SLMAP3 is ubiquitously expressed and has been linked to cardiomyopathy, Brugada syndrome and Hippo signaling. To examine any role in cardiogenesis, mice homozygous for floxed slmap allele were crossed with Nkx2.5-cre mice to nullify its expression in cardiac progenitors. Targeted deletion of the slmap gene resulted in the specific knockout (KO) of the SLMAP3 (~91 KDa) isoform without any changes in the expression of the SLMAP2 (~43 kDa) or the SLMAP1 (~35 kDa) isoforms which continued to accumulate to similar levels as seen in Wt embryonic hearts. The loss of SLMAP3 from cardiac progenitors resulted in decreased size of the developing embryonic hearts evident at E9.5 to E16.5 with four small chambers and significantly thinner left ventricles. The proliferative capacity assessed with the phosphorylation of histone 3 or with Ki67 in E12.5 hearts was not significantly altered due to SLMAP3 deficiency. The size of embryonic cardiomyocytes, marked with anti-Troponin C, revealed significantly smaller cells, but their hypertrophic response (AKT1 and MTOR1) was not significantly affected by the specific loss of SLMAP3 protein. Further, no changes in phosphorylation of MST1/2 or YAP were detected in SLMAP3-KO embryonic myocardium, ruling out any impact on Hippo signaling. Rat embryonic cardiomyocytes express the three SLMAP isoforms and their knockdown (KD) with sh-RNA, resulted in decreased proliferation and enhanced senescence but without any impact on Hippo signaling. Collectively, these data show that SLMAP is critical for normal cardiac development with potential for the various isoforms to serve compensatory roles. Our data imply novel mechanisms for SLMAP action in cardiac growth independent of Hippo signaling.


Assuntos
Via de Sinalização Hippo , Miocárdio , Camundongos , Ratos , Animais , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas de Membrana/metabolismo , Isoformas de Proteínas/metabolismo
12.
Int J Mol Sci ; 25(14)2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39063130

RESUMO

Carbapenemase-producing Enterobacterales are increasingly being recognized in nosocomial infections. The performance of a flow cytometry-based rapid assay for their detection and differentiation was evaluated. This is a disruptive phenotypic technology, phenotypic and growth-independent, that searches for the lesions produced by drugs acting on cells after a short incubation time. Overall, 180 Gram-negative bacteria were studied, and results were compared with those obtained molecularly by PCR and phenotypically by 'KPC, MBL and OXA-48 Confirm Kit'. This phenotypic method was used as reference for comparison purposes. Susceptibility to carbapenems (imipenem, meropenem, and ertapenem) was determined by standard broth microdilution. Overall, 112 isolates (62.2%) were carbapenemase producers, 41 KPCs, 36 MßLs, and 31 OXA-48, and 4 strains were KPC + MßL co-producers. Sixty-eight isolates were carbapenemase-negative. The percentage of agreement, sensitivity, and specificity were calculated according to ISO 20776-2:2021. The FASTinov assay showed 97.7% agreement with the reference method for carbapenemase detection. Discrepant flow cytometry results were obtained in four isolates compared with both reference and PCR results. The sensitivity and specificity of this new technology were 95.3% and 98.5%, respectively, for KPCs, 97.6% and 99.3% for MßLs, and 96.9% and 98% for OXA-48 detection. In conclusion, we describe a rapid flow cytometry assay with high accuracy for carbapenemase detection and the differentiation of various carbapenemases, which should impact clinical microbiology laboratories and patient management.


Assuntos
Proteínas de Bactérias , Citometria de Fluxo , Testes de Sensibilidade Microbiana , beta-Lactamases , beta-Lactamases/metabolismo , Citometria de Fluxo/métodos , Proteínas de Bactérias/metabolismo , Humanos , Testes de Sensibilidade Microbiana/métodos , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/enzimologia , Antibacterianos/farmacologia , Sensibilidade e Especificidade , Carbapenêmicos/farmacologia
13.
J Cancer Educ ; 39(4): 426-436, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38592656

RESUMO

The European Oncology Nursing Society (EONS) is a pan-European not for profit society involving approximately 28,000 cancer nurses from 32 countries in the region. The European College of Cancer Nursing (ECCN) exists under the umbrella of EONS and was established in 2020 with a strategic priority to develop, promote and deliver educational opportunities for nurses across Europe. ECCN introduced a pilot on-line education programme for 20 nurses in January 2023. This study evaluated participating nurses' views and experience of learning on the pilot programme. The study adopted a mixed method approach guided by the four levels of the Kirkpatrick theoretical framework. A dominant focus on qualitative data was used with supplementary quantitative data. The Standards for Reporting Qualitative Research (SRQR) was followed. Eleven nurses completed the pre-pilot online questionnaire (response rate 65%) and seven (n = 7) completed the post-pilot questionnaire (41% response rate). Five (n = 5) nurses participated in two focus group interviews. Data analysis resulted in the development of four overarching themes: A wider world of cancer nursing; Shapeless mentorship; Impact on Practice; Learning online and what now? On commencement of online education programmes, nurses value a structured timetable and support from nursing management to maximise engagement with the learning materials.


Assuntos
Enfermagem Oncológica , Humanos , Projetos Piloto , Enfermagem Oncológica/educação , Europa (Continente) , Grupos Focais , Inquéritos e Questionários , Pesquisa Qualitativa , Educação a Distância , Feminino , Masculino , Adulto
14.
Psychogeriatrics ; 24(5): 1111-1119, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39039430

RESUMO

BACKGROUND: Falls are directly related to morbidity and mortality of older people. Multifactorial approaches that are individualised and based on fall risk factors are necessary. This study aims to verify the effects of a case management-based intervention on non-motor risk factors for falls in community-dwelling older people with a history of falls. METHODS: The intervention applied a multidimensional assessment of risk factors for falls, a discussion about the identified risk factors, the preparation of an individualised plan with the participant, and the application, monitoring and review of the plan. RESULTS: There was a significant interaction between groups and assessments only in the visuospatial domain (P = 0.031). After simple main effects analysis, differences between groups and assessments were not significant, although there was a tendency of worse visuospatial performance in the control group in the follow-up assessment (P = 0.099). There were no significant differences between groups or between assessments in other variables. CONCLUSION: The intervention has the potential to maintain non-motor risk factors for falls in community-dwelling older people with a history of falls. However, more clinical trials are needed to prove its effects.


Assuntos
Acidentes por Quedas , Administração de Caso , Vida Independente , Humanos , Acidentes por Quedas/prevenção & controle , Acidentes por Quedas/estatística & dados numéricos , Idoso , Masculino , Feminino , Fatores de Risco , Idoso de 80 Anos ou mais , Avaliação Geriátrica/métodos
15.
Eur J Immunol ; 52(6): 946-957, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35307819

RESUMO

The nature of the immune responses associated with COVID-19 pathogenesis and disease severity, as well as the breadth of vaccine coverage and duration of immunity, is still unclear. Given the unpredictability for developing a severe/complicated disease, there is an urgent need in the field for predictive biomarkers of COVID-19. We have analyzed IgG Fc N-glycan traits of 82 SARS-CoV-2+ unvaccinated patients, at diagnosis, by nano-LC-ESI-MS. We determined the impact of IgG Fc glyco-variations in the induction of NK cells activation, further evaluating the association between IgG Fc N-glycans and disease severity/prognosis. We found that SARS-CoV-2+ individuals display, at diagnosis, variations in the glycans composition of circulating IgGs. Importantly, levels of galactose and sialic acid structures on IgGs are able to predict the development of a poor COVID-19 disease. Mechanistically, we demonstrated that a deficiency on galactose structures on IgG Fc in COVID-19 patients appears to induce NK cells activation associated with increased release of IFN-γ and TNF-α, which indicates the presence of pro-inflammatory immunoglobulins and higher immune activation, associated with a poor disease course. This study brings to light a novel blood biomarker based on IgG Fc glycome composition with capacity to stratify patients at diagnosis.


Assuntos
COVID-19 , Biomarcadores , COVID-19/diagnóstico , Teste para COVID-19 , Galactose , Glicosilação , Humanos , Fragmentos Fc das Imunoglobulinas , Imunoglobulina G , Polissacarídeos , SARS-CoV-2 , Índice de Gravidade de Doença
16.
Inorg Chem ; 62(13): 5207-5218, 2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-36940386

RESUMO

Lanthanide-ligand complexes are key components of technological applications, and their properties depend on their structures in the solution phase, which are challenging to resolve experimentally or computationally. The coordination structure of the Eu3+ ion in different coordination environments in acetonitrile is examined using ab initio molecular dynamics (AIMD) simulations and extended X-ray absorption fine structure (EXAFS) spectroscopy. AIMD simulations are conducted for the solvated Eu3+ ion in acetonitrile, both with or without a terpyridyl ligand, and in the presence of either triflate or nitrate counterions. EXAFS spectra are calculated directly from AIMD simulations and then compared to experimentally measured EXAFS spectra. In acetonitrile solution, both nitrate and triflate anions are shown to coordinate directly to the Eu3+ ion forming either ten- or eight-coordinate solvent complexes where the counterions are binding as bidentate or monodentate structures, respectively. Coordination of a terpyridyl ligand to the Eu3+ ion limits the available binding sites for the solvent and anions. In certain cases, the terpyridyl ligand excludes any solvent binding and limits the number of coordinated anions. The solution structure of the Eu-terpyridyl complex with nitrate counterions is shown to have a similar arrangement of Eu3+ coordinating molecules as the crystal structure. This study illustrates how a combination of AIMD and EXAFS can be used to determine how ligands, solvent, and counterions coordinate with the lanthanide ions in solution.

17.
J Immunol ; 207(6): 1591-1598, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34417260

RESUMO

COVID-19 is a highly selective disease in which SARS-CoV-2 infection can result in different clinical manifestations ranging from asymptomatic/mild to severe disease that requires hospitalization. In this study, we demonstrated that SARS-CoV-2 infection results in a glycosylation reprogramming of circulating lymphocytes at diagnosis. We identified a specific glycosignature of T cells, defined upon SARS-CoV-2 infection and apparently triggered by a serological factor. This specific glycan switch of T cells is detected at diagnosis being more pronounced in asymptomatic patients. We further demonstrated that asymptomatic patients display an increased expression of a viral-sensing receptor through the upregulation of DC-SIGN in monocytes. We showed that higher levels of DC-SIGN in monocytes at diagnosis correlates with better COVID-19 prognosis. This new evidence pave the way to the identification of a novel glycan-based response in T cells that may confer protection against SARS-CoV-2 infection in asymptomatic patients, highlighting a novel prognostic biomarker and potential therapeutic target.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Polissacarídeos , Receptores Virais , Linfócitos T
18.
BMC Pediatr ; 23(1): 533, 2023 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-37884935

RESUMO

BACKGROUND: The association between fetal growth restriction (FGR) and childhood neurodevelopmental delay is unclear and the evidence available to the present date shows conflicting results. Our aim was to analyse the impact of early-onset FGR on the neurodevelopmental outcome at 24 months of corrected age in very preterm infants. METHODS: Retrospective cohort study of very preterm infants (≤ 32 weeks' gestation) admitted to a neonatal intensive care unit between 1 January 2013-31 December 2019. The control group comprised appropriate for gestational age (AGA) newborns. Griffiths III Mental Development Scale was performed at 24 months of corrected age. RESULTS: 132 infants were included: 44 FGR and 88 AGA. Mean Global Development Quotient (GDQ) was lower for FGR infants (p = 0.004) even after adjusting for maternal and perinatal factors (ßadjusted -16.703; p = 0.009). The average scores for the neurodevelopmental domains were highest for personal-social-emotional skills (107.02 ± 16.34), followed by eye/hand coordination (105.61 ± 14.20) and foundation of learning skills (102.23 ± 13.74) and were lowest for gross motor (97.90 ± 11.88) and language/communication skills (96.39 ± 18.88). FGR had a significant negative impact on all domains except for gross motor skills. After adjustment, FGR continued to have a significant adverse impact on language/communication (ßadjusted -21.924; p = 0.013), eye/hand coordination (ßadjusted -15.446; p = 0.015) and foundation of learning skills (ßadjusted -15.211; p = 0.013). CONCLUSIONS: In very preterm infants, FGR was associated with a significantly increased risk of poor neurodevelopmental outcome at 24 months of corrected age compared to age-matched AGA infants.


Assuntos
Retardo do Crescimento Fetal , Doenças do Prematuro , Lactente , Gravidez , Feminino , Recém-Nascido , Humanos , Criança , Retardo do Crescimento Fetal/etiologia , Recém-Nascido Prematuro , Estudos Retrospectivos , Recém-Nascido de muito Baixo Peso , Idade Gestacional
19.
An Acad Bras Cienc ; 95(1): e20201480, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37132745

RESUMO

Banana preserve is produced by mixing the puree of the fruit with sucrose and organic acids. However, concerns about body esthetics or health reasons have encouraged the search for low-calorie products. Therefore, the objective of this study was to evaluate the effect of calcium chloride (CaCl2), carrageenan gum, and low methoxyl pectin (LM-pectin) on the physicochemical and sensory characteristics of sugar-free banana preserves. By using a central composite rotational design (CCRD) of 2³ + 6 axial points + 4 central points, we obtained 18 formulations that were further tested. Lower CaCl2 concentrations (0.54% to 0.61%) resulted in preserves with lower pH and more vivid color. The increased concentration of LM-pectin (1.40% to 1.64%) resulted in formulations with a yellowish-red hue and with lower moisture, thus, reducing the flavor and purchase intention of the product. Higher concentrations of carrageenan gum (1.04% to 1.15%) decreased the perception of banana preserve aroma. Therefore, concentrations of CaCl2 ranging from 0.54% to 0.61%, carrageenan gum ranging from 0.74% to 0.89% and LM-pectin ranging from 1.40% to 1.64% resulted in sugar-free banana preserves with ideal sweetness and consistency and were, therefore, more acceptable.


Assuntos
Musa , Cloreto de Cálcio , Carragenina , Pectinas/farmacologia , Frutas
20.
Int J Mol Sci ; 24(7)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37047406

RESUMO

Traumatic spinal cord injury (SCI) initiates a cascade of cellular events, culminating in irreversible tissue loss and neuroinflammation. After the trauma, the blood vessels are destroyed. The blood-spinal cord barrier (BSCB), a physical barrier between the blood and spinal cord parenchyma, is disrupted, facilitating the infiltration of immune cells, and contributing to a toxic spinal microenvironment, affecting axonal regeneration. Understanding how the vascular constituents of the BSCB respond to injury is crucial to prevent BSCB impairment and to improve spinal cord repair. Here, we focus our attention on the vascular transcriptome at 3- and 7-days post-injury (dpi), during which BSCB is abnormally leaky, to identify potential molecular players that are injury-specific. Using the mouse contusion model, we identified Cd9 and Mylip genes as differentially expressed at 3 and 7 dpi. CD9 and MYLIP expression were injury-induced on vascular cells, endothelial cells and pericytes, at the injury epicentre at 7 dpi, with a spatial expression predominantly at the caudal region of the lesion. These results establish CD9 and MYLIP as two new potential players after SCI, and future studies targeting their expression might bring promising results for spinal cord repair.


Assuntos
Células Endoteliais , Traumatismos da Medula Espinal , Camundongos , Animais , Células Endoteliais/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Pericitos/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Barreira Hematoencefálica/metabolismo
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