Exploring the tilted accretion disc of AQ Men with TESS

AQ Men is a nova-like variable that is presumed to have a tilted, precessing accretion disc. Grazing eclipses in this system have been speculated to be useful in exploring the geometry of its accretion disc. In this work, we analysed Transiting Exoplanet Survey Satellite (TESS) observations of AQ Men, which provide the best light curve of this object thus far. We show that the depths of the eclipses are changing with the orientation of the accretion disc, which means that they can serve as a direct test of the tilted accretion disc models. The precession period of the accretion disc is increasing during the TESS observations. However, it is still shorter than the period determined in the previous studies. The amplitude of the variability related to the precession of the accretion disc varies, and so does the shape of this variability. Moreover, we have detected a positive superhump that was previously unseen in AQ Men. Interestingly, the positive superhump has a strongly non-sinusoidal shape, which is not expected for a nova-like variable

Prominent role for T cell-derived Tumour Necrosis Factor for sustained control of Mycobacterium tuberculosis infection

Tumour Necrosis Factor (TNF) is critical for host control of M. tuberculosis, but the relative contribution of TNF from innate and adaptive immune responses during tuberculosis infection is unclear. Myeloid versus T-cell-derived TNF function in tuberculosis was investigated using cell type-specific TNF deletion. Mice deficient for TNF expression in macrophages/neutrophils displayed early, transient susceptibility to M. tuberculosis but recruited activated, TNF-producing CD4+ and CD8+ T-cells and controlled chronic infection. Strikingly, deficient TNF expression in T-cells resulted in early control but susceptibility and eventual mortality during chronic infection with increased pulmonary pathology. TNF inactivation in both myeloid and T-cells rendered mice critically susceptible to infection with a phenotype resembling complete TNF deficient mice, indicating that myeloid and T-cells are the primary TNF sources collaborating for host control of tuberculosis. Thus, while TNF from myeloid cells mediates early immune function, T-cell derived TNF is essential to sustain protection during chronic tuberculosis infection

GM-CSF Priming Drives Bone Marrow-Derived Macrophages to a Pro-Inflammatory Pattern and Downmodulates PGE(2) in Response to TLR2 Ligands

In response to pathogen recognition by Toll-like receptors (TLRs) on their cell surface, macrophages release lipid mediators and cytokines that are widely distributed throughout the body and play essential roles in host responses. Granulocyte macrophage colony-stimulating factor (GM-CSF) is important for the immune response during infections to improve the clearance of microorganisms. In this study, we examined the release of mediators in response to TLR2 ligands by bone marrow-derived macrophages (BMDMs) primed with GM-CSF. We demonstrated that when stimulated with TLR2 ligands, non-primed BMDMs preferentially produced PGE(2) in greater amounts than LTB4. However, GM-CSF priming shifted the release of lipid mediators by BMDMs, resulting in a significant decrease of PGE(2) production in response to the same stimuli. The decrease of PGE(2) production from primed BMDMs was accompanied by a decrease in PGE-synthase mRNA expression and an increase in TNF-alpha and nitric oxide (NO) production. Moreover, some GM-CSF effects were potentiated by the addition of IFN-gamma. Using a variety of TLR2 ligands, we established that PGE(2) release by GM-CSF-primed BMDMs was dependent on TLR2 co-receptors (TLR1, TLR6), CD14, MyD88 and the nuclear translocation of NF kappa B but was not dependent on peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation. Indeed, GM-CSF priming enhanced TLR2, TLR4 and MyD88 mRNA expression and phospho-I kappa B alpha formation. These findings demonstrate that GM-CSF drives BMDMs to present a profile relevant to the host during infections.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)FAPESP - Fundacao de Amparo a Pesquisa do Estado de Sao PauloConselho Nacional de Pesquisa (CNPq)CNPq - Conselho Nacional de Pesquis

H19 Antisense RNA Can Up-Regulate Igf2 Transcription by Activation of a Novel Promoter in Mouse Myoblasts

It was recently shown that a long non-coding RNA (lncRNA), that we named the 91H RNA (i.e. antisense H19 transcript), is overexpressed in human breast tumours and contributes in trans to the expression of the Insulin-like Growth Factor 2 (IGF2) gene on the paternal chromosome. Our preliminary experiments suggested that an H19 antisense transcript having a similar function may also be conserved in the mouse. In the present work, we further characterise the mouse 91H RNA and, using a genetic complementation approach in H19 KO myoblast cells, we show that ectopic expression of the mouse 91H RNA can up-regulate Igf2 expression in trans despite almost complete unmethylation of the Imprinting-Control Region (ICR). We then demonstrate that this activation occurs at the transcriptional level by activation of a previously unknown Igf2 promoter which displays, in mouse tissues, a preferential mesodermic expression (Pm promoter). Finally, our experiments indicate that a large excess of the H19 transcript can counteract 91H-mediated Igf2 activation. Our work contributes, in conjunction with other recent findings, to open new horizons to our understanding of Igf2 gene regulation and functions of the 91H/H19 RNAs in normal and pathological conditions

Mycobacterial PIMs Inhibit Host Inflammatory Responses through CD14-Dependent and CD14-Independent Mechanisms

Mycobacteria develop strategies to evade the host immune system. Among them, mycobacterial LAM or PIMs inhibit the expression of pro-inflammatory cytokines by activated macrophages. Here, using synthetic PIM analogues, we analyzed the mode of action of PIM anti-inflammatory effects. Synthetic PIM1 isomer and PIM2 mimetic potently inhibit TNF and IL-12 p40 expression induced by TLR2 or TLR4 pathways, but not by TLR9, in murine macrophages. We show inhibition of LPS binding to TLR4/MD2/CD14 expressing HEK cells by PIM1 and PIM2 analogues. More specifically, the binding of LPS to CD14 was inhibited by PIM1 and PIM2 analogues. CD14 was dispensable for PIM1 and PIM2 analogues functional inhibition of TLR2 agonists induced TNF, as shown in CD14-deficient macrophages. The use of rough-LPS, that stimulates TLR4 pathway independently of CD14, allowed to discriminate between CD14-dependent and CD14-independent anti-inflammatory effects of PIMs on LPS-induced macrophage responses. PIM1 and PIM2 analogues inhibited LPS-induced TNF release by a CD14-dependent pathway, while IL-12 p40 inhibition was CD14-independent, suggesting that PIMs have multifold inhibitory effects on the TLR4 signalling pathway

Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addresse

Host-pathogen interactions : role of pattern recognition receptors (PRR) for the induction of the host immune response in response to mycobacteria and modulation of this response by mycobacterial components

Nos travaux ont permis d’étudier différents aspects des interactions hôte-pathogènes. L’étude de différents Pattern Recognition Receptors (PRR) autres que les TLR, ainsi que leurs associations a mis en évidence une redondance partielle entre les récepteurs des familles des Scavenger Receptors, lectines de type C et EMR1 in vitro et in vivo dans l’induction de la réponse immunitaire à Mycobacterium tuberculosis. Cette compensation entre les récepteurs contraste avec les rôles indépendants et non redondants des cytokines et de leurs voies associées comme le TNF, l’IL-1R1, L’IFNγR et MyD88, indispensables pour le contrôle de l’infection. Grâce à l’utilisation de nouvelles souris génétiquement modifiées, nous avons pu montrer un rôle minime de la lymphotoxine α dans le contrôle de l’infection par Mycobacterium tuberculosis contrairement au rôle primordial du TNF. Enfin, notre étude s’est poursuivie avec l’analyse de la modulation de la réponse immunitaire de l’hôte par des composants de la paroi des mycobactéries, les PIM. L’élaboration de PIM synthétiques a permis de montrer que ces molécules de faibles poids moléculaires inhibent l’induction des voies TLR4 et TLR2 et possèdent ainsi un potentiel anti-inflammatoire thérapeutique.In these study, we aimed to investigate different aspects of the host-pathogen interactions. We investigated the involvement of various Pattern Recognition Receptors (PRR) other than TLR, and their associations for the control of M. tuberculosis infection. We highlighted a partial redundancy between members of the Scavenger Receptors family, C-type lectins and EMR1 in response to mycobacteria in vitro and in vivo. This is in sharp contrast with the cytokine pathways like TNF, IL-1R1, IFNγR and MyD88, essentials to control M. tuberculosis infection and which cannot compensate with each other. By using new genetically deficient mice, we showed a limited role for the lymphotoxin α in the control of the infection by Mycobacterium tuberculosis in contrast with the vital role for TNF. Finally, we analysed the modulation of the immune response by mycobacterial cell wall components, PIM. Use of synthetic PIM demonstrated that these small molecules exert an inhibitory activity on TLR4- and TLR2-signaling pathways and may have a therapeutic anti-inflammatory potential

Host-pathogen interactions : role of pattern recognition receptors (PRR) for the induction of the host immune response in response to mycobacteria and modulation of this response by mycobacterial components

Nos travaux ont permis d’étudier différents aspects des interactions hôte-pathogènes. L’étude de différents Pattern Recognition Receptors (PRR) autres que les TLR, ainsi que leurs associations a mis en évidence une redondance partielle entre les récepteurs des familles des Scavenger Receptors, lectines de type C et EMR1 in vitro et in vivo dans l’induction de la réponse immunitaire à Mycobacterium tuberculosis. Cette compensation entre les récepteurs contraste avec les rôles indépendants et non redondants des cytokines et de leurs voies associées comme le TNF, l’IL-1R1, L’IFNγR et MyD88, indispensables pour le contrôle de l’infection. Grâce à l’utilisation de nouvelles souris génétiquement modifiées, nous avons pu montrer un rôle minime de la lymphotoxine α dans le contrôle de l’infection par Mycobacterium tuberculosis contrairement au rôle primordial du TNF. Enfin, notre étude s’est poursuivie avec l’analyse de la modulation de la réponse immunitaire de l’hôte par des composants de la paroi des mycobactéries, les PIM. L’élaboration de PIM synthétiques a permis de montrer que ces molécules de faibles poids moléculaires inhibent l’induction des voies TLR4 et TLR2 et possèdent ainsi un potentiel anti-inflammatoire thérapeutique.In these study, we aimed to investigate different aspects of the host-pathogen interactions. We investigated the involvement of various Pattern Recognition Receptors (PRR) other than TLR, and their associations for the control of M. tuberculosis infection. We highlighted a partial redundancy between members of the Scavenger Receptors family, C-type lectins and EMR1 in response to mycobacteria in vitro and in vivo. This is in sharp contrast with the cytokine pathways like TNF, IL-1R1, IFNγR and MyD88, essentials to control M. tuberculosis infection and which cannot compensate with each other. By using new genetically deficient mice, we showed a limited role for the lymphotoxin α in the control of the infection by Mycobacterium tuberculosis in contrast with the vital role for TNF. Finally, we analysed the modulation of the immune response by mycobacterial cell wall components, PIM. Use of synthetic PIM demonstrated that these small molecules exert an inhibitory activity on TLR4- and TLR2-signaling pathways and may have a therapeutic anti-inflammatory potential

Intéractions hôte-pathogène (rôle des pattern recognition receptors (PRR) dans l'induction de la réponse immunitaire aux mycobactéries et modulation de cette réponse par des composés mycobactériens)

Nos travaux ont permis d étudier différents aspects des interactions hôte-pathogènes. L étude de différents Pattern Recognition Receptors (PRR) autres que les TLR, ainsi que leurs associations a mis en évidence une redondance partielle entre les récepteurs des familles des Scavenger Receptors, lectines de type C et EMR1 in vitro et in vivo dans l induction de la réponse immunitaire à Mycobacterium tuberculosis. Cette compensation entre les récepteurs contraste avec les rôles indépendants et non redondants des cytokines et de leurs voies associées comme le TNF, l IL-1R1, L IFNgR et MyD88, indispensables pour le contrôle de l infection. Grâce à l utilisation de nouvelles souris génétiquement modifiées, nous avons pu montrer un rôle minime de la lymphotoxine a dans le contrôle de l infection par Mycobacterium tuberculosis contrairement au rôle primordial du TNF. Enfin, notre étude s est poursuivie avec l analyse de la modulation de la réponse immunitaire de l hôte par des composants de la paroi des mycobactéries, les PIM. L élaboration de PIM synthétiques a permis de montrer que ces molécules de faibles poids moléculaires inhibent l induction des voies TLR4 et TLR2 et possèdent ainsi un potentiel anti-inflammatoire thérapeutique.In these study, we aimed to investigate different aspects of the host-pathogen interactions. We investigated the involvement of various Pattern Recognition Receptors (PRR) other than TLR, and their associations for the control of M. tuberculosis infection. We highlighted a partial redundancy between members of the Scavenger Receptors family, C-type lectins and EMR1 in response to mycobacteria in vitro and in vivo. This is in sharp contrast with the cytokine pathways like TNF, IL-1R1, IFNgR and MyD88, essentials to control M. tuberculosis infection and which cannot compensate with each other. By using new genetically deficient mice, we showed a limited role for the lymphotoxin a in the control of the infection by Mycobacterium tuberculosis in contrast with the vital role for TNF. Finally, we analysed the modulation of the immune response by mycobacterial cell wall components, PIM. Use of synthetic PIM demonstrated that these small molecules exert an inhibitory activity on TLR4- and TLR2-signaling pathways and may have a therapeutic anti-inflammatory potential.ORLEANS-SCD-Bib. electronique (452349901) / SudocSudocFranceF