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1.
Medicine (Baltimore) ; 99(44): e22557, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126304

RESUMO

To evaluate the performance of different blood cells-derived indexes in the diagnosis of rheumatoid arthritis (RA).Neutrophil-to-lymphocyte ratio (NLR), lymphocyte to monocyte ratio, platelet to lymphocyte ratio (PLR), systemic inflammation response index (SIRI), and aggregate inflammation systemic index were calculated in 199 consecutive RA patients and 283 sex and age-matched controls (147 healthy donors and 136 patients with other rheumatic diseases). Area under the curve (AUCs), sensitivity and specificity were calculated to evaluate the accuracy of indexes in discriminating between RA and controls. Association between indexes and RA variables was explored by multiple linear regression analyses.Blood cells-derived indexes did not demonstrate good accuracy in differentiating RA from controls with lymphocyte to monocyte ratio, the index with the best diagnostic performance, having 63.6% of sensitivity and 65.3% specificity [AUC (95%CI) = 0.67 (0.62-0.72]. The accuracy of the indexes in differentiating RA from healthy donors was significantly higher than that (AUCs < 0.6 for all comparisons) differentiating RA from rheumatic diseases. In RA, SIRI and aggregate inflammation systemic index showed significant association with C-reactive protein and erythrocyte sedimentation rate.Our results do not support the use of blood cells-derived indexes for the diagnosis of RA, suggesting that they might reflect chronic inflammatory burden in rheumatic diseases rather than, specifically, in RA.


Assuntos
Artrite Reumatoide/diagnóstico , Contagem de Células Sanguíneas/estatística & dados numéricos , Índice de Gravidade de Doença , Área Sob a Curva , Células Sanguíneas/metabolismo , Plaquetas , Sedimentação Sanguínea , Proteína C-Reativa , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Inflamação/sangue , Contagem de Linfócitos , Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos , Neutrófilos , Contagem de Plaquetas , Sensibilidade e Especificidade
2.
J Vis Exp ; (162)2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32894265

RESUMO

In this study, the hemocompatibility of tubes with an inner diameter of 5 mm made of polyvinyl chloride (PVC) and coated with different bioactive conjugates was compared to uncoated PVC tubes, latex tubes, and a stent for intravascular application that was placed inside the PVC tubes. Evaluation of hemocompatibility was done using an in vitro hemodynamic loop model that is recommended by the ISO standard 10993-4. The tubes were cut into segments of identical length and closed to form loops avoiding any gap at the splice, then filled with human blood and rotated in a water bath at 37 °C for 3 hours. Thereafter, the blood inside the tubes was collected for the analysis of whole blood cell count, hemolysis (free plasma hemoglobin), complement system (sC5b-9), coagulation system (fibrinopeptide A), and leukocyte activation (polymorphonuclear elastase, tumor necrosis factor and interleukin-6). Host cell activation was determined for platelet activation, leukocyte integrin status and monocyte platelet aggregates using flow cytometry. The effect of inaccurate loop closure was examined with x-ray microtomography and scanning electron microscopy, that showed thrombus formation at the splice. Latex tubes showed the strongest activation of both plasma and cellular components of the blood, indicating a poor hemocompatibility, followed by the stent group and uncoated PVC tubes. The coated PVC tubes did not show a significant decrease in platelet activation status, but showed an increased in complement and coagulation cascade compared to uncoated PVC tubes. The loop model itself did not lead to the activation of cells or soluble factors, and the hemolysis level was low. Therefore, the presented in vitro hemodynamic loop model avoids excessive activation of blood components by mechanical forces and serves as a method to investigate in vitro interactions between donor blood and vascular medical devices.


Assuntos
Células Sanguíneas/metabolismo , Prótese Vascular , Materiais Revestidos Biocompatíveis/química , Hemodinâmica/fisiologia , Teste de Materiais/métodos , Células Sanguíneas/citologia , Coagulação Sanguínea , Proteínas do Sistema Complemento/metabolismo , Humanos , Teste de Materiais/normas , Modelos Biológicos , Plasma/metabolismo , Ativação Plaquetária , Cloreto de Polivinila/química
3.
PLoS One ; 15(8): e0237143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760165

RESUMO

OBJECTIVES: Abatacept acts as a competitive inhibitor of the CD28/(CD80/86) costimulation signal required for T cell activation. Mechanisms of action of abatacept have not been fully investigated. The objective of this study was to provide detailed insight into the mode of action of Abatacept based on gene expression data. METHODS: In this ancillary study from the APPRAISE trial, we investigated the global molecular effects of Abatacept in whole blood samples collected prospectively in biologic naive rheumatoid arthritis patients (n = 19) at baseline and 6 months after the initiation of Abatacept therapy concomitant with methotrexate. Whole human genome microarrays (4x44K) were performed on both baseline and 6-month samples from responders and non-responders patients categorized according to EULAR criteria. T-test with Benjamini-Hochberg correction was performed to identify significant gene expression changes. Gene Ontology and Single Experiment Analysis tools allowed us to highlight specific biological mechanisms involved in methotrexate/Abatacept. RESULTS: In methotrexate/Abatacept responders, 672 genes were significantly (q<0.05) dysregulated at 6 months compared to baseline. Correlation analysis highlighted 19 genes whose dysregulations were significantly associated with disease activity variation (p<0.05) and whose functions were associated with proliferation, apoptosis of cells and mitochondrial metabolism, suggesting a restoration of oxidative signaling. The other 653 gene expression changes were relative to direct or indirect effects of methotrexate/Abatacept treatment and were significantly (p<0.005) involved in pathways relative to mRNA processing, proteasome, angiogenesis, apoptosis and TCR signaling. This study highlights new mechanisms of action of methotrexate/Abatacept and may provide new therapeutic targets to prevent autoimmunity in rheumatoid arthritis.


Assuntos
Abatacepte/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Metotrexato/farmacologia , Transcriptoma/efeitos dos fármacos , Abatacepte/administração & dosagem , Abatacepte/uso terapêutico , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade
4.
BMC Bioinformatics ; 21(1): 324, 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32693778

RESUMO

BACKGROUND: Modern developments in single-cell sequencing technologies enable broad insights into cellular state. Single-cell RNA sequencing (scRNA-seq) can be used to explore cell types, states, and developmental trajectories to broaden our understanding of cellular heterogeneity in tissues and organs. Analysis of these sparse, high-dimensional experimental results requires dimension reduction. Several methods have been developed to estimate low-dimensional embeddings for filtered and normalized single-cell data. However, methods have yet to be developed for unfiltered and unnormalized count data that estimate uncertainty in the low-dimensional space. We present a nonlinear latent variable model with robust, heavy-tailed error and adaptive kernel learning to estimate low-dimensional nonlinear structure in scRNA-seq data. RESULTS: Gene expression in a single cell is modeled as a noisy draw from a Gaussian process in high dimensions from low-dimensional latent positions. This model is called the Gaussian process latent variable model (GPLVM). We model residual errors with a heavy-tailed Student's t-distribution to estimate a manifold that is robust to technical and biological noise found in normalized scRNA-seq data. We compare our approach to common dimension reduction tools across a diverse set of scRNA-seq data sets to highlight our model's ability to enable important downstream tasks such as clustering, inferring cell developmental trajectories, and visualizing high throughput experiments on available experimental data. CONCLUSION: We show that our adaptive robust statistical approach to estimate a nonlinear manifold is well suited for raw, unfiltered gene counts from high-throughput sequencing technologies for visualization, exploration, and uncertainty estimation of cell states.


Assuntos
Dinâmica não Linear , RNA-Seq , Análise de Célula Única/métodos , Células Sanguíneas/metabolismo , Regulação da Expressão Gênica , Humanos , Modelos Genéticos , Neurônios/metabolismo , Distribuição Normal , Análise de Componente Principal , Fatores de Tempo
5.
PLoS One ; 15(7): e0236118, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32667943

RESUMO

The objective of this study was to evaluate whether pre-weaning heifer calves divergent for residual feed intake (RFI) or residual feed intake and body weight gain (RIG) exhibit differences in thermography, blood, and ruminal parameters. Thirty-two Gyr heifer calves were enrolled in a 63-d trial and classified into 2 feed efficiency (FE) groups based on RFI and RIG (mean ± 0.5 SD). The groups were classified as high efficiency (HE) RFI (HE RFI, n = 9), HE RIG (HE RIG, n = 10), low efficiency (LE) RFI (LE RFI, n = 10), and LE RIG (LE RIG, n = 11). The amount of whole milk provided for each calf was calculated based on their metabolic weight at birth (42% x BW0.75). The liquid diet was divided into two meals at 0700 and 1400 h. The total solid diet (TSD) was composed of 92% concentrate and 8% of Tifton 85 hay chopped in 5-cm lengths, as fed. Intake was measured daily. Blood concentrations of insulin, beta hydroxybutyrate, urea, and glucose, and ruminal pH, N-NH3, and volatile fatty acids (VFA) were evaluated at 14, 28, 42, 56, and 70 days of age. Thermal images of the calves were taken with an infrared camera (FLIR T420, FLIR Systems Inc., Wilsonville, OR) on d 56 (±3) at 0600 h, before the morning feeding. Total VFA concentration and propionate as % of total VFA were 24.2% and 22.2% lower in HE RFI compared to LE RFI calves, respectively. On the other hand, acetate as % of total VFA was 10.6% greater in HE RFI than LE RFI calves. Blood urea concentration tended to be greater in LE RFI than HE RFI calves. High efficiency HE RIG tended to have 6.8% greater acetate and 15.4% lower propionate as % of total VFA than LE RIG. Blood insulin concentration was greater and blood glucose tended to be greater for LE RIG than HE RIG group. Low efficiency RIG group had greater left rib, left flank, and anus surface temperature measured by infrared thermography than the HE RIG group. Differences in ruminal fermentation do not seem to be associated with pre-weaning calves efficiency, while differences in protein metabolism seem to affect RFI during this phase. Infrared thermography appears to be correlated to RIG in pre-weaning heifer calves.


Assuntos
Ração Animal/análise , Dieta/veterinária , Comportamento Alimentar/fisiologia , Termogênese , Desmame , Ganho de Peso , Animais , Células Sanguíneas/metabolismo , Bovinos , Ingestão de Energia , Ruminantes/metabolismo , Termografia
6.
PLoS Biol ; 18(3): e3000643, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32176686

RESUMO

Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are by individual molecules such as cytokines carried by blood, by neural transmission, or, in more severe pathologies, by the entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs), but the parameters that determine their uptake are unknown. Using varied animal models that stimulate neuronal activity by peripheral inflammation, optogenetics, and selective proteasome inhibition of dopaminergic (DA) neurons, we show that the transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object placement. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.


Assuntos
Células Sanguíneas/citologia , Encéfalo/metabolismo , Vesículas Extracelulares/metabolismo , Inflamação/metabolismo , Animais , Células Sanguíneas/metabolismo , Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Feminino , Hipocampo/fisiologia , Inflamação/induzido quimicamente , Ácido Caínico/farmacologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos Transgênicos , Optogenética , Complexo de Endopeptidases do Proteassoma/metabolismo , Transdução de Sinais , Técnicas Estereotáxicas , Ubiquitina/metabolismo
7.
BMC Bioinformatics ; 21(1): 115, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32183713

RESUMO

BACKGROUND: In vertebrate genomes, CpG sites can be clustered into CpG islands, and the amount of methylation in a CpG island can change due to gene regulation processes. Thus, single regulatory events can simultaneously change the methylation states of many CpG sites within a CpG island. This should be taken into account when quantifying the amount of change in methylation, for example in form of a branch length in a phylogeny of cell types. RESULTS: We propose a probabilistic model (the IWE-SSE model) of methylation dynamics that accounts for simultaneous methylation changes in multiple CpG sites belonging to the same CpG island. We further propose a Markov-chain Monte-Carlo (MCMC) method to fit this model to methylation data from cell type phylogenies and apply this method to available data from murine haematopoietic cells and from human cell lines. Combined with simulation studies, these analyses show that accounting for CpG island wide methylation changes has a strong effect on the inferred branch lengths and leads to a significantly better model fit for the methylation data from murine haematopoietic cells and human cell lines. CONCLUSION: The MCMC based parameter estimation method for the IWE-SSE model in combination with our MCMC based inference method allows to quantify the amount of methylation changes at single CpG sites as well as on entire CpG islands. Accounting for changes affecting entire islands can lead to more accurate branch length estimation in the presence of simultaneous methylation change.


Assuntos
Ilhas de CpG , Metilação de DNA , Modelos Estatísticos , Animais , Células Sanguíneas/metabolismo , Regulação da Expressão Gênica , Humanos , Cadeias de Markov , Camundongos , Método de Monte Carlo , Filogenia
8.
Sci Rep ; 10(1): 4464, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161272

RESUMO

Adenosine is widely known as a potent modulator of innate and acquired immunity. It is released during transplants, and acts on four subtype receptors. In previous studies, we demonstrated that pharmacological preconditioning (PPC), pre-administration of the selective A1 receptor (A1R) agonist led to A1R desensitization, is followed by upregulation of the adenosine A2A receptor. This immunosuppressive effect resulted in lymphopenia, and it reduced T-cell reactivity. The aim of the current study was to challenge the immunosuppressive effects of A1R-PPC in models of allogeneic grafts. PPC mice were treated by intraperitoneal injection using specific adenosine A1R agonist 24 h and 12 h before starting any procedure. We challenged our method in novel allogeneic muscle and skin grafts models. Mice and grafts were assessed by complete blood counts, MLR from PPC splenocytes, and pathological evaluation. We found a significant reduction in WBC and lymphocyte counts in PPC-treated mice. Two-way MLR with splenocytes from PPC grafted mice showed decreased proliferation and anergy. Histology of PPC allogeneic grafts revealed profoundly less infiltration and even less muscle necrosis compared to vehicle treated allografts. Similar results observed in PPC skin transplantation. To conclude, PPC moderated graft rejection in separate allogeneic challenges, and reduced lymphocytes infiltration and ischemic damage.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Imunossupressão , Imunossupressores/farmacologia , Condicionamento Pré-Transplante , Animais , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/imunologia , Células Sanguíneas/metabolismo , Proliferação de Células , Camundongos , Modelos Animais , Receptor A1 de Adenosina/metabolismo , Transplante de Pele , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
9.
Am J Pathol ; 190(5): 958-967, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084363

RESUMO

Cortactin is an actin-binding protein expressed in virtually all cell types. It regulates several cell functions, including adhesion and migration. Cortactin overexpression is associated with increased metastasis formation and worse outcome in different types of solid tumors, thus highlighting a critical role of cortactin in cancer progression. Mechanistically, this is due to increased invadopodia formation and matrix metalloproteinase secretion. Cortactin has been until recently considered absent in hematopoietic cells because these cells express the cortactin homolog hematopoietic cell-specific lyn substrate-1. However, many recent reports describe functional expression of cortactin in different hematopoietic cells, such as macrophages, dendritic cells, and lymphocytes. Of note, cortactin is strongly overexpressed in leukemic cell lines and primary patient-derived leukemic cells. In B-cell chronic lymphocytic leukemia, this is associated with poor prognosis and increased chemotaxis; in B-cell acute lymphoblastic leukemia, high cortactin levels correlate with treatment failure and relapse. Moreover, cortactin has been proposed as a diagnostic marker for non-Hodgkin B-cell lymphomas. This review summarizes current knowledge on cortactin expression in hematopoietic cells and discusses the functional implications for different hematological malignancies.


Assuntos
Células Sanguíneas/metabolismo , Cortactina/metabolismo , Neoplasias Hematológicas/metabolismo , Animais , Adesão Celular/fisiologia , Movimento Celular/fisiologia , Humanos
10.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165714, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32023482

RESUMO

Blood-cell targeting Autoimmune Diseases (BLADs) are complex diseases that affect blood cell formation or prevent blood cell production. Since these clinical conditions are gathering growing attention, experimental approaches are being used to investigate the mechanisms behind their pathogenesis and to identify proteins associated with them. However, computational approaches have not been utilized extensively in the study of BLADs. This study aims to investigate the interaction network of proteins associated with BLADs (BLAD interactome) and to identify novel associations with other human proteins. The method followed in this study combines information regarding protein-protein interaction network properties and autoimmune disease terms. Proteins with high network scores and statistically significant autoimmune disease term enrichment were obtained and 14 of them were designated as candidate proteins associated with BLADs. Additionally, clustering analysis of the BLAD interactome was used and allowed the detection of 17 proteins that act as "connectors" of different BLADs. We expect our findings to further extend experimental efforts for the investigation of the pathogenesis and the relationships of BLADs.


Assuntos
Doenças Autoimunes/imunologia , Células Sanguíneas/imunologia , Doenças Hematológicas/imunologia , Mapeamento de Interação de Proteínas/métodos , Mapas de Interação de Proteínas/imunologia , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Autoantígenos/imunologia , Autoantígenos/metabolismo , Doenças Autoimunes/sangue , Biomarcadores/análise , Biomarcadores/sangue , Biomarcadores/metabolismo , Células Sanguíneas/metabolismo , Análise por Conglomerados , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Doenças Hematológicas/sangue , Hematopoese/imunologia , Humanos
11.
Int J Mol Sci ; 21(3)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32012663

RESUMO

Biodosimetry is a useful method for estimating personal exposure doses to ionizing radiation. Studies have identified metabolites in non-cellular biofluids that can be used as markers in biodosimetry. Levels of metabolites in blood cells may reflect health status or environmental stresses differentially. Here, we report changes in the levels of murine blood cell metabolites following exposure to X-rays in vivo. Levels of blood cell metabolites were measured by capillary electrophoresis time-of-flight mass spectrometry. The levels of 100 metabolites were altered substantially following exposure. We identified 2-aminobutyric acid, 2'-deoxycytidine, and choline as potentially useful markers of radiation exposure and established a potential prediction panel of the exposure dose using stepwise regression. Levels of blood cell metabolites may be useful biomarkers in estimating exposure doses during unexpected radiation incidents.


Assuntos
Biomarcadores , Células Sanguíneas/metabolismo , Células Sanguíneas/efeitos da radiação , Eletroforese Capilar , Radiação Ionizante , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Dose-Resposta à Radiação , Metaboloma , Metabolômica/métodos
12.
Int J Parasitol ; 50(3): 195-208, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32087247

RESUMO

The Manila clam (Ruditapes philippinarum) is the bivalve species with the highest global production from both fisheries and aquaculture, but its production is seriously threatened by perkinsosis, a disease caused by the protozoan parasite Perkinsus olseni. To understand the molecular mechanisms underlying R. philippinarum-P. olseni interactions, we analysed the gene expression profiles of in vitro challenged clam hemocytes and P. olseni trophozoites, using two oligo-microarray platforms, one previously validated for R. philippinarum hemocytes and a new one developed and validated in this study for P. olseni. Manila clam hemocytes were in vitro challenged with trophozoites, zoospores, and extracellular products from P. olseni in vitro cultures, while P. olseni trophozoites were in vitro challenged with Manila clam plasma along the same time-series (1 h, 8 h, and 24 h). The hemocytes showed a fast activation of the innate immune response, particularly associated with hemocyte recruitment, in the three types of challenges. Nevertheless, different immune-related pathways were activated in response to the different parasite stages, suggesting specific recognition mechanisms. Furthermore, the analyses provided useful complementary data to previous in vivo challenges, and confirmed the potential of some proposed biomarkers. The combined analysis of gene expression in host and parasite identified several processes in both the clam and P. olseni, such as redox and glucose metabolism, protease activity, apoptosis and iron metabolism, whose modulation suggests cross-talk between parasite and host. This information might be critical to determine the outcome of the infection, thus highlighting potential therapeutic targets. Altogether, the results of this study aid understanding the response and interaction between R. philippinarum and P. olseni, and will contribute to developing effective control strategies for this threatening parasitosis.


Assuntos
Alveolados , Bivalves/parasitologia , Alveolados/genética , Alveolados/metabolismo , Animais , Bivalves/genética , Bivalves/metabolismo , Células Sanguíneas/metabolismo , Interações Hospedeiro-Parasita/imunologia , Imunidade Inata , Técnicas In Vitro/métodos , Parasitos/genética , Parasitos/metabolismo , Frutos do Mar/parasitologia , Transcriptoma , Trofozoítos/genética , Trofozoítos/metabolismo
13.
Carbohydr Polym ; 230: 115629, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887898

RESUMO

The research described here focused on the effect of sulfated red algal polysaccharides (κ-, κ/ß-, ι/κ-carrageenan) individually and in combination with lipopolysaccharide (LPS) on the synthesis of prostaglandin E2 (PGE2) and cytokines (interleukin [IL]-1ß and IL-6) in whole blood model in vitro. The results demonstrated that, at high concentrations, carrageenans have substantial ability to modulate PGE2 synthesis and stimulate IL-1ß and IL-6 synthesis. A low degree of sulfate and high molecular weight were a prerequisite for the ability of carrageenans to modulate PGE2 synthesis. Further, we investigated the ability of the carrageenans alone and in combination with casein to affect bile salt permeability through an artificial membrane imitating the gastrointestinal barrier. The least sulfated κ/ß-carrageenan could retain bile salt permeation the most but less efficiently than cholestyramine. The polysaccharides did not affect pancreatic lipase activity. Our data confirm a possible mechanism of the cholesterol-reducing properties of carrageenan.


Assuntos
Carragenina/farmacologia , Dinoprostona/biossíntese , Lipase/metabolismo , Ácidos e Sais Biliares/metabolismo , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Carragenina/química , Permeabilidade da Membrana Celular , Células Cultivadas , Humanos , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Metabolismo dos Lipídeos
14.
Nat Commun ; 11(1): 247, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937773

RESUMO

Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, using single cell transcriptomics, we identify a specific location-associated composition and transcriptome of CSF leukocytes. Multiple sclerosis (MS) - an autoimmune disease of the CNS - increases transcriptional diversity in blood, but increases cell type diversity in CSF including a higher abundance of cytotoxic phenotype T helper cells. An analytical approach, named cell set enrichment analysis (CSEA) identifies a cluster-independent increase of follicular (TFH) cells potentially driving the known expansion of B lineage cells in the CSF in MS. In mice, TFH cells accordingly promote B cell infiltration into the CNS and the severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate ongoing local T/B cell interaction.


Assuntos
Líquido Cefalorraquidiano/imunologia , Leucócitos/imunologia , Esclerose Múltipla/imunologia , Animais , Linfócitos B/imunologia , Células Sanguíneas/metabolismo , Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Perfilação da Expressão Gênica , Humanos , Leucócitos/metabolismo , Camundongos , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Fenótipo , Análise de Célula Única , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
15.
J Biomed Sci ; 27(1): 25, 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31954402

RESUMO

BACKGROUND: Dengue presents a wide clinical spectrum. Most patients recover following a self-limiting non-severe clinical course. A small proportion of patients progress to severe disease, mostly characterized by plasma leakage with or without hemorrhage. Early symptoms of severe dengue (SD) are similar to those of non-severe dengue fever (DF). Severe symptoms manifest after 3-5 days of fever, which can be life threatening due to lack of proper medications and inability to distinguish severe cases during the early stages. Early prediction of SD in patients with no warning signs who may later develop severe infection is very important for proper disease management to alleviate related complications and mortality. microRNA are small non-coding RNA molecules that regulate post-transcriptional gene expression. Due to the remarkable stability and the role of microRNA in gene expression, altered expression of microRNA was evaluated to explore clinically relevant prognostic markers of severe dengue. METHODS: The relative expression of microRNA hsa-let-7e (let-7e), hsa-miR-30b-5p (miR-30b), hsa-miR-30e-3p (miR-30e), hsa-miR-33a (miR-33a), and hsa-miR-150-5p (miR-150) and several putative target genes in peripheral blood cells (PBC) collected from 20 DF and 20 SD positive patients within 4 days from fever onset was evaluated by quantitative reverse transcription PCR (qRT-PCR). RESULTS: miR-150 showed significant (P < 0.01) up regulation in PBC of SD patients compared to DF patients during the acute phase of infection. Expression of enhancer of zeste homolog 2 (EZH2) was significantly (P < 0.01) down regulated indicating that genes involved in epigenetic regulation are also differentially expressed in SD patients during the early stage of infection. CONCLUSIONS: Differential expression of microRNA miR-150 and the putative target gene EZH2 may serve as reliable biomarkers of disease severity during early stages of dengue infection.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Expressão Gênica , Marcadores Genéticos , MicroRNAs/genética , Dengue Grave/diagnóstico , Adulto , Células Sanguíneas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
16.
Mater Sci Eng C Mater Biol Appl ; 106: 110298, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753336

RESUMO

Cancer is a leading cause of mortality worldwide. Cell membrane-coated nanocarriers actively targeting tumor sites are known to circumvent the limitations of conventional treatments and nanosized drug delivery systems. Cell membrane-coated nanocarriers can evade the immune system and can target tumors, thereby exhibiting a prolonged circulation time, enhancing tumor accumulation, increasing cancer therapeutic efficacy, and facilitating tumor imaging in vivo. Numerous studies have focused on cell membrane-coated nanocarriers homing to tumors. The use of these biomimetic nanocarriers in combination with photothermal or photodynamic cancer therapy have received increasing attention. This review discusses various sources of cell membranes, which have been harnessed previously in this field and highlights the mechanism underlying the targeting action of these nanocarriers and the method of their extraction, along with the applications of biomimetic cell membrane-coated nanocarriers in cancer phototherapy and diagnosis. Finally, this review discusses prospects in methods to resist cancer metastasis.


Assuntos
Membrana Celular/química , Portadores de Fármacos/química , Nanopartículas/química , Animais , Bactérias/metabolismo , Materiais Biomiméticos/química , Células Sanguíneas/citologia , Células Sanguíneas/metabolismo , Parede Celular/química , Humanos , Linfócitos/citologia , Linfócitos/metabolismo
17.
Science ; 366(6472)2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31857451

RESUMO

Blood is the predominant source for molecular analyses in humans, both in clinical and research settings. It is the target for many therapeutic strategies, emphasizing the need for comprehensive molecular maps of the cells constituting human blood. In this study, we performed a genome-wide transcriptomic analysis of protein-coding genes in sorted blood immune cell populations to characterize the expression levels of each individual gene across the blood cell types. All data are presented in an interactive, open-access Blood Atlas as part of the Human Protein Atlas and are integrated with expression profiles across all major tissues to provide spatial classification of all protein-coding genes. This allows for a genome-wide exploration of the expression profiles across human immune cell populations and all major human tissues and organs.


Assuntos
Células Sanguíneas/metabolismo , Transcriptoma , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Proteínas/genética
18.
PLoS One ; 14(11): e0224448, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31693680

RESUMO

BACKGROUND: The mechanisms explaining multimorbidity between asthma, dermatitis and rhinitis (allergic multimorbidity) are not well known. We investigated these mechanisms and their specificity in distinct cell types by means of an interactome-based analysis of expression data. METHODS: Genes associated to the diseases were identified using data mining approaches, and their multimorbidity mechanisms in distinct cell types were characterized by means of an in silico analysis of the topology of the human interactome. RESULTS: We characterized specific pathomechanisms for multimorbidities between asthma, dermatitis and rhinitis for distinct emergent non-eosinophilic cell types. We observed differential roles for cytokine signaling, TLR-mediated signaling and metabolic pathways for multimorbidities across distinct cell types. Furthermore, we also identified individual genes potentially associated to multimorbidity mechanisms. CONCLUSIONS: Our results support the existence of differentiated multimorbidity mechanisms between asthma, dermatitis and rhinitis at cell type level, as well as mechanisms common to distinct cell types. These results will help understanding the biology underlying allergic multimorbidity, assisting in the design of new clinical studies.


Assuntos
Asma/imunologia , Dermatite Alérgica de Contato/imunologia , Dermatite Atópica/imunologia , Mapas de Interação de Proteínas/imunologia , Rinite Alérgica/imunologia , Asma/epidemiologia , Asma/genética , Células Sanguíneas/imunologia , Células Sanguíneas/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Conjuntos de Dados como Assunto , Dermatite Alérgica de Contato/epidemiologia , Dermatite Alérgica de Contato/genética , Dermatite Atópica/epidemiologia , Dermatite Atópica/genética , Perfilação da Expressão Gênica , Humanos , Imunidade Celular/genética , Multimorbidade , Mapas de Interação de Proteínas/genética , Rinite Alérgica/epidemiologia , Rinite Alérgica/genética
20.
PLoS One ; 14(11): e0224835, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31703101

RESUMO

Metformin is a commonly used antihyperglycaemic agent for the treatment of type 2 diabetes mellitus. Nevertheless, the exact mechanisms of action, underlying the various therapeutic effects of metformin, remain elusive. The goal of this study was to evaluate the alterations in longitudinal whole-blood transcriptome profiles of healthy individuals after a one-week metformin intervention in order to identify the novel molecular targets and further prompt the discovery of predictive biomarkers of metformin response. Next generation sequencing-based transcriptome analysis revealed metformin-induced differential expression of genes involved in intestinal immune network for IgA production and cytokine-cytokine receptor interaction pathways. Significantly elevated faecal sIgA levels during administration of metformin, and its correlation with the expression of genes associated with immune response (CXCR4, HLA-DQA1, MAP3K14, TNFRSF21, CCL4, ACVR1B, PF4, EPOR, CXCL8) supports a novel hypothesis of strong association between metformin and intestinal immune system, and for the first time provide evidence for altered RNA expression as a contributing mechanism of metformin's action. In addition to universal effects, 4 clusters of functionally related genes with a subject-specific differential expression were distinguished, including genes relevant to insulin production (HNF1B, HNF1A, HNF4A, GCK, INS, NEUROD1, PAX4, PDX1, ABCC8, KCNJ11) and cholesterol homeostasis (APOB, LDLR, PCSK9). This inter-individual variation of the metformin effect on the transcriptional regulation goes in line with well-known variability of the therapeutic response to the drug.


Assuntos
Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Metformina/farmacologia , Transcriptoma , Adulto , Biomarcadores , Ensaios Clínicos como Assunto , Biologia Computacional/métodos , Fezes/química , Feminino , Voluntários Saudáveis , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Receptores Fc , Adulto Jovem
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