Natural killer cell activation by dendritic cells: balancing inhibitory and activating signals

Natural killer (NK) cells have originally been identified by their spontaneous cytolytic potential against tumor cells, which, however, might result from pre-activation due to prior pathogen exposure. Resting NK cells, on the contrary, require activation by bystander antigen-presenting cells to reach their full functional competence. In this review, we will summarize studies on how dendritic cells (DCs), the most potent type of antigen-presenting cell, communicate with human NK cells to activate them in secondary lymphoid organs and to integrate signals from activated NK cells at sites of inflammation for their own maturation. Furthermore, we will review aspects of the immunological synapse, which mediates this cross-talk. These studies provide the mechanistic understanding of how mature DCs can activate NK cells and survive to go on for the activation of adaptive immunity. This feature of DCs, to activate different waves of immune responses, could be harnessed for immunotherapies, including vaccination

Cytoskeletal stabilization of inhibitory interactions in immunologic synapses of mature human dendritic cells with natural killer cells

Human mature dendritic cells (DCs) can efficiently stimulate natural killer (NK)-cell responses without being targeted by their cytotoxicity. To understand this important regulatory crosstalk, we characterized the development of the immunologic synapse between mature DCs and resting NK cells. Conjugates between these 2 innate leukocyte populations formed rapidly, persisted for prolonged time periods and matured with DC-derived f-actin polymerization at the synapse. Polarization of IL-12 and IL-12R to the synapse coincided with f-actin polymerization, while other activating and inhibitory molecules were enriched at the interface between DCs and NK cells earlier. Functional assays revealed that inhibition of f-actin polymerization in mature synapses led to an increase of IFN-γ secretion and cytotoxicity by NK cells. This elevated NK-cell reactivity resulted from decreased inhibitory signaling in the absence of MHC class I polarization at the interface, which was observed on inhibition of f-actin polymerization in DCs. Thus, inhibitory signaling is stabilized by f-actin at the synapse between mature DCs and resting NK cells

Impaired IFN-γ production and proliferation of NK cells in Multiple Sclerosis

NK cells are multicompetent lymphocytes of the innate immune system with a central role in host defense and immune regulation. Studies in experimental animal models of multiple sclerosis (MS) provided evidence for both pathologic and protective effects of NK cells. Humans harbor two functionally distinct NK-cell subsets exerting either predominantly cytotoxic (CD56dimCD16+) or immunoregulatory (CD56brightCD16−) functions. We analyzed these two subsets and their functions in the peripheral blood of untreated patients with relapsing-remitting MS compared with healthy blood donors. While ex vivo frequencies of CD56brightCD16− and CD56dimCD16+ NK cells were similar in patients and controls, we found that cytokine-driven in vitro accumulation and IFN-γ production of CD56brightCD16− NK cells but not of their CD56dimCD16+ counterparts were substantially diminished in MS. Impaired expansion of CD56brightCD16− NK cells was cell intrinsic because the observed effects could be reproduced with purified NK cells in an independent cohort of patients and controls. In contrast, cytolytic NK-cell activity toward the human erythromyeloblastoid leukemia cell line K562, the allogeneic CD4+ T cell line CEM and allogeneic primary CD4+ T-cell blasts was unchanged. Thus, characteristic functions of CD56brightCD16− NK cells, namely cytokine-induced NK cell expansion and IFN-γ production, are compromised in the NK cell compartment of MS patient

Translation and cross-cultural adaptation of the Seizure Severity Questionnaire: first results

INTRODUCTION: Seizure severity and seizure frequency reduction are the goals in the treatment of epilepsy. Up to the present, there are no validated instruments or studies emphasizing initial reliability and validity of questionnaires to measure seizure severity into Brazilian Portuguese. PURPOSE: This report describes the translation and cross-cultural adaptation of the Seizure Severity Questionnaire (SSQ), an instrument to evaluate seizure frequency and severity. CASUISTIC AND METHODS: The author conceded the original English version to Portuguese translation. Later, two independent native English-speaking teachers fluent in Portuguese translated this consensus version back into English. Comparison of the back-translation with the original English version showed only a few discrepancies, and the English and Portuguese versions were considered conceptually equivalent. Thirty patients regularly treated with temporal lobe epilepsy related to mesial temporal sclerosis answered the questionnaire. RESULTS: Twenty-two adult patients (73%) were male and mean age 37. Ten (33%) reported only auras and 18 Movements or attitudes during the seizures. Two presented Loss of consciousness. For 13 (43%) there was a long time to recuperate after the event. 12 reported Emotional effects and all patients had Body effects. The majority of patients, 28 (94%) considered their seizures extremely severe and for 23 (77%) the recuperation period was the most bother symptom. The association of seizure frequency and Nottingham Health Profile showed statistical significance for the domains: Emotional well-being (p = 0.046), Pain (p = 0.015) and Sleep (p = 0.003). CONCLUSION: This study explored the cultural adaptation of SSQ and its first results. We also assessed the correlation between seizure frequency and quality of life impact. The instrument SSQ could help to understand the seizure concern in the view of the patient.INTRODUÇÃO: O tratamento medicamentoso tem como meta principal a redução da freqüência de crises ou seu controle completo. No Brasil não dispomos de informação sobre tradução, adaptação cultural e validação de escalas que medem a gravidade de crises. OBJETIVO: Tradução e adaptação cultural da Escala de Gravidade de Crises (EGC) (Seizure Severity Questionnaire) com objetivo de avaliar o impacto da freqüência de crises. CASUÍSTICA E METODOLOGIA: A autora da escala concedeu a versão original em inglês para a tradução. Dois professores de inglês nativos realizaram a retrotradução. As versões em português e a retrotraduzida foram comparadas à original e após consenso foi obtida a versão final. Trinta pacientes em tratamento regular com diagnóstico de epilepsia do lobo temporal relacionada a esclerose mesial temporal responderam ao questionário. RESULTADOS: Vinte e dois pacientes (73%) eram do sexo masculino, com média de idade de 37 anos. Na Escala de Gravidade de Crises, 10 (33%) tiveram apenas auras; 18 (62%) apresentaram Movimentos ou atitudes durante a crise. Dois (6%) apresentaram Perda dos sentidos, 13 (43%) revelaram demora na recuperação após a crise com Efeitos mentais e corpóreos e 12 (40%) tiveram Efeitos emocionais. Vinte e oito (94%) responderam terem sido as crises extremamente graves e para 23 (77%) a recuperação após as crises foi o que mais incomodou. Observou-se uma correlação estatisticamente significante entre a freqüência de crises e os domínios do Nottingham Health Profile: Reações Emocionais (p = 0,046), Dor (p = 0,015) e Alterações do sono (p = 0,003). CONCLUSÃO: Foi realizada a adaptação cultural da EGC, avaliando seus resultados preliminares, e a relação entre freqüência de crises e QV. O impacto das crises tradicionalmente estudado em termos da freqüência e tipo de evento pode ser melhor compreendido se analisado sob a ótica do paciente.Universidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

Biochemical profile and in vitro neuroprotective properties of Carpobrotus edulis L., a medicinal and edible halophyte native to the coast of South Africa

This work reports the nutritional profile and in vitro neuroprotective properties of leaves of Carpobrotus edulis L, a medicinal and edible succulent species native to the coast of South Africa. Biomass was evaluated for proximate composition and for contents in carotenoids, liposoluble pigments and minerals. Hexane, dichloromethane, ethyl acetate and methanol extracts were prepared by Soxhlet extraction from dried biomass and evaluated for in vitro inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), capacity to attenuate hydrogen peroxide (H2O2)-induced injury in the human dopaminergic cell line SH-SY5Y and for anti-neuroinflammatory potential on lipopolysaccharide (LPS)-stimulated microglia cells. Extracts were evaluated for antioxidant activity by four complementary methods, total content of phenolics, tannins and flavonoids. Finally the profile of the main phenolic compounds was determined by high performance liquid chromatography with diode array detection (HPLC-DAD). C edulis has a high moisture content, high levels of crude protein, fibre, ash, carotenoids, calcium and iron and a low fat level. The extracts were able to efficiently scavenge the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH), reduce iron and chelate copper and iron ions, and exhibited different levels of phenolic compounds in the order ethyl acetate > methanol > dichloromethane > hexane. The main compounds detected were gallic and salicylic acids and quercetin, all in the ethyl acetate extract. The extracts allowed a dual and potent inhibition of AChE and BuChE. The dichloromethane and methanol extracts had the strongest capacity to prevent cell death induced by H2O2, and the methanol extract had anti-neuronflammatory properties. All together our results suggest that consumption of leaves of C edulis can contribute for a balanced diet, and that they may add to the improvement of cognitive functions. It also suggests possible novel biotechnological applications of C. edulis such as source of molecules and/or products for the food and/or pharmaceutical industries. Studies aiming to the isolation and identification of the bioactive compounds are already in progress. (C) 2017 SAAB. Published by Elsevier B.V. All rights reserved.Portuguese National BudgetXtremeGourmet project [ALG-01-0247-FEDER-017676]FCT Investigator Programme [IF/00049/2012]info:eu-repo/semantics/publishedVersio

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Measurement of Dipeptidylpeptidase Activity in vitro and in vivo

International audienceDipeptidylpeptidases (DPPs) are serine proteases, which cleave small proteins and peptides possessing a proline or an alanine in the second position of their N-terminus. Among the members of this family, dipeptidylpeptidase 4 (DPP4) is constitutively expressed in the extracellular space. DPP4 is found at the surface of many hematopoietic and non-hematopoietic cells and is also present in many biological fluids in a bioactive soluble form. DPP4 expression is modulated by inflammation, and measurements of its activity have been used as biomarker for disease. Here, we describe a method to evaluate the enzymatic activity of DPP4 in vitro and in vivo