5,172 research outputs found
Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues
This study was designed to investigate the functional heterogeneity of human Th17 and how their plasticity shapes the nature of immune cell responses to inflammation and autoimmune diseases, such as systemic lupus erythematosus (SLE). We evaluated functional Th17 cell subsets based on the profile of cytokine production in peripheral blood (PB), bone marrow aspirates (BM) and lymph node biopsies (LN) from healthy individuals (n = 35) and PB from SLE patients (n = 34). Data were analysed by an automated method for merging and calculation of flow cytometric data, allowing us to identify eight Th17 subpopulations. Normal BM presented lower frequencies of Th17 (p = 0.006 and p = 0.05) and lower amount of IL-17 per cell (p = 0.03 and p = 0.02), compared to normal PB and LN biopsies. In the latter tissues were found increased proportions of Th17 producing TNF-α or TNF-α/IL-2 or IFN-γ/TNF-α/IL-2, while in BM, Th17 producing other cytokines than IL-17 was clearly decreased. In SLE patients, the frequency of Th17 was higher than in control, but the levels of IL-17 per cell were significantly reduced (p < 0.05). Among the eight generated subpopulations, despite the great functional heterogeneity of Th17 in SLE, a significant low proportion of Th17 producing TNF-α was found in inactive SLE, while active SLE showed a high proportion producing only IL-17. Our findings support the idea that the functional heterogeneity of Th17 cells could depend on the cytokine microenvironment, which is distinct in normal BM as well as in active SLE, probably due to a Th1/Th2 imbalance previously reported by our group
Influence of the nycthemeral cycle on the roosting behaviour of the Orange-winged Amazon
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Environmental stimuli exert important effects on the expression of the endogenous rhythms. Daily movements of groups of parrots in response to the light/dark cycle have been studied by several researchers. However, the factors modifying the intrinsic rhythmicity of this behaviour remain little known. This study describes how the nychthemeral/circadian periodicity of roost daily movements of the Orange-winged Amazon Amazona amazonica is modified by weather factors. Numbers of parrots arriving or leaving the roosting site llha dos Papagaios were determined on a minute by minute basis. More parrots have significantly arrived at the roost after sunset than before, while more parrots have significantly left the roost before sunrise than after. The peak exodus of parrots occurred at 23 +/- 5.24 minutes before sunrise, when the average light intensity was 1 lux. The peak influx of parrots occurred at 6 +/- 6.1 minutes after sunset, when the average light intensity was 50 lux. By altering ambient light intensity, weather conditions have significantly influenced the arrival and departure times, with parrots leaving later and arriving earlier when conditions were overcast at the roost site.842509515PARATURCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES
Três rearranjos diferentes, três fenótipos diferentes :Estudo Familiar Cromossoma 14
Introdução – Cromossomas derivativos são o resultado de rearranjos estruturais que
tanto podem ocorrer num só, como entre dois ou mais cromossomas. Estes rearranjos
dão origem a cromossomas estruturalmente anormais, podendo resultar um fenótipo
normal ou mais ou menos grave, dependendo do tipo de anomalia encontrada.
Materiais e métodos – Caso índex: homem de 55 anos, referenciado para estudos de
citogenética clássica (cariótipo com bandas GTG de alta resolução) e molecular
(MLPA – kits P036 e P070 e FISH com sonda subtelomérica especifica para o
cromossoma 14) por apresentar um quadro clínico de atraso mental. Posteriormente
realizaram-se estudos citogenéticos a uma irmã com atraso cognitivo e baixa estatura,
e a mais quatro familiares com fenótipos normais.
Resultados – O cariótipo do caso índex revelou a existência de uma anomalia
cromossómica estrutural desequilibrada num dos cromossomas 14, sugerindo uma
deleção da banda 14q32, e uma duplicação do braço curto localizada na parte terminal
do braço longo. Nos estudos de citogenética molecular, a técnica de MLPA identificou
uma deleção da região subtelomérica no braço longo do cromossoma 14, em ambos
os kits e, posteriormente, a técnica de FISH comprovou essa deleção.
Após estudos familiares, concluiu-se que dois dos irmãos apresentavam anomalias
cromossómicas distintas do caso índex, envolvendo igualmente o cromossoma 14.
Apesar de não ser possível efetuar o cariótipo à mãe (falecida), presume-se que estas
alterações tenham tido origem numa anomalia cromossómica materna, uma vez que o
pai deste indivíduo apresentava um cariótipo normal.
Conclusões – Os autores apresentam os resultados citogenéticos dos vários
indivíduos estudados, e realçam a raridade da existência de três rearranjos diferentes
(um deles aparentemente equilibrado e dois desequilibrados), envolvendo o
cromossoma 14, encontrados numa mesma família
Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action
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Previous issue date: 2014Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, BrazilUniversidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, BrazilUniversidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, BrazilInstituto Militar de Engenharia. Laboratório de Modelagem Molecular Aplicada à Defesa Química e Biológica. Rio de Janeiro, RJ, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, BrazilBackground: Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated.
Methods: Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro. The CQAns were re-evaluated against CQ-resistant and -sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human (HssLDH) or plasmodial lactate dehydrogenase (PfLDH) enzymes, and, a β-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro.
Results: All tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half-maximal inhibitory concentration (IC50) values below 1 μΜ. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of PfLDH; specificity between the residues involved in H-bonds of the PfLDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of PfLDH. CQAn33 and CQAn37 inhibited β-haematin formation with either a similar or a 2-fold higher IC50 value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei, reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive.
Conclusions: The presence of an alkyne group and the size of the side chain affected anti-P. falciparum activityin vitro. Docking studies suggested a mechanism of action other than PfLDH inhibition. The β-haematin assay suggested the presence of an additional mechanism of action of CQAn33 and CQAn37. Tests with CQAn34, CQAn37, CQAn39 and CQAn45 confirmed previous results against P. berghei malaria in mice, and CQAn33, 39 and 45 were active against CQ-resistant parasites, but CQAn28 and CQAn34 were not. The result likely reflects structure-activity relationships related to the resistant phenotype
Social prescribing : a ‘natural’ community-based solution
This paper discusses social prescribing as part of the wider NHS England universal personalised care model, and it describes how community nurses can engage with social prescribing systems to support community resilience. A case study based on the example of gardening, as a nature-based social prescription provided by the RHS Bridgewater Wellbeing Garden, is provided to illustrate the scope, reach and impact of non-medical, salutogenic approaches for community practitioners. The authors argue that social prescribing and, in particular, nature-based solutions, such as gardening, can be used as a non-medical asset-based approach by all health professionals working in the community as a way to promote health and wellbeing. They consider how the negative impact of social distancing resulting from COVID-19 restrictions could be diluted through collaboration between a holistic, social prescribing system and community staff. The paper presents a unique perspective on how community nurses can collaborate with link workers through social prescribing to help combat social isolation and anxiety and support resilience
A biophysical model of cell adhesion mediated by immunoadhesin drugs and antibodies
A promising direction in drug development is to exploit the ability of
natural killer cells to kill antibody-labeled target cells. Monoclonal
antibodies and drugs designed to elicit this effect typically bind cell-surface
epitopes that are overexpressed on target cells but also present on other
cells. Thus it is important to understand adhesion of cells by antibodies and
similar molecules. We present an equilibrium model of such adhesion,
incorporating heterogeneity in target cell epitope density and epitope
immobility. We compare with experiments on the adhesion of Jurkat T cells to
bilayers containing the relevant natural killer cell receptor, with adhesion
mediated by the drug alefacept. We show that a model in which all target cell
epitopes are mobile and available is inconsistent with the data, suggesting
that more complex mechanisms are at work. We hypothesize that the immobile
epitope fraction may change with cell adhesion, and we find that such a model
is more consistent with the data. We also quantitatively describe the parameter
space in which binding occurs. Our results point toward mechanisms relating
epitope immobility to cell adhesion and offer insight into the activity of an
important class of drugs.Comment: 13 pages, 5 figure
Weibel-Palade bodies at a glance
The vascular environment can rapidly alter, and the speed with which responses to both physiological and pathological changes are required necessitates the existence of a highly responsive system. The endothelium can quickly deliver bioactive molecules by regulated exocytosis of its secretory granules, the Weibel−Palade bodies (WPBs). WPBs include proteins that initiate both haemostasis and inflammation, as well those that modulate blood pressure and angiogenesis. WPB formation is driven by von Willebrand factor, their most abundant protein, which controls both shape and size of WPBs. WPB are generated in a range of sizes, with the largest granules over ten times the size of the smallest. In this Cell Science at a Glance and the accompanying poster, we discuss the emerging mechanisms by which WPB size is controlled and how this affects the ability of this organelle to modulate haemostasis. We will also outline the different modes of exocytosis and their polarity that are currently being explored, and illustrate that these large secretory organelles provide a model for how elements of secretory granule biogenesis and exocytosis cooperate to support a complex and diverse set of functions
Tolerogenic versus Inflammatory Activity of Peripheral Blood Monocytes and Dendritic Cells Subpopulations in Systemic Lupus Erythematosus
Abnormalities in monocytes and in peripheral blood dendritic cells (DC) subsets have been reported in systemic lupus erythematosus (SLE). We aim to clarify the tolerogenic or inflammatory role of these cells based on ICOSL or IFN-α and chemokine mRNA expression, respectively, after cell purification. The study included 18 SLE patients with active disease (ASLE), 25 with inactive disease (ISLE), and 30 healthy controls (HG). In purified plasmacytoid DC (pDC) was observed a lower ICOSL mRNA expression in ASLE and an increase in ISLE; similarly, a lower ICOSL mRNA expression in monocytes of ALSE patients was found. However, a higher ICOSL mRNA expression was observed in ASLE compared to HG in myeloid DCs. Interestingly, clinical parameters seem to be related with ICOSL mRNA expression. Regarding the inflammatory activity it was observed in purified monocytes and CD14(-/low) CD16(+) DCs an increase of CCL2, CXCL9, and CXCL10 mRNA expression in ASLE compared to HG. In myeloid DC no differences were observed regarding chemokines, and IFN-α mRNA expression. In pDC, a higher IFN-α mRNA expression was observed in ASLE. Deviations in ICOSL, chemokine, and IFN-α mRNA expression in peripheral blood monocytes and dendritic cells subpopulations in SLE appear to be related to disease activity
Poor youths and ‘pacification’:dilemmas between discourse and practice from the perspective of young people about policing in Rio de Janeiro’s favelas
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