LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms

<p>Abstract</p> <p>Background</p> <p>IL-10 is a cytokine mainly produced by macrophages that plays key roles in tolerance to inhaled antigens and in lung homeostasis. Its regulation in alveolar macrophages (HAM), the resident lung phagocytes, remains however unknown.</p> <p>Methods</p> <p>The present study investigated the role of intracellular signalling and transcription factors controlling the production of IL-10 in LPS-activated HAM from normal nonsmoking volunteers.</p> <p>Results</p> <p>LPS (1–1000 pg/ml) induced <it>in vitro </it>IL-10 production by HAM, both at mRNA and protein levels. LPS also activated the phosphorylation of ERK, p38 and JNK MAPkinases (immunoblots) and Sp-1 nuclear activity (EMSA). Selective inhibitors of MAPKinases (respectively PD98059, SB203580 and SP600125) and of Sp-1 signaling (mithramycin) decreased IL-10 expression in HAM. In addition, whilst not affecting IL-10 mRNA degradation, the three MAPKinase inhibitors completely abolished Sp-1 activation by LPS in HAM.</p> <p>Conclusion</p> <p>These results demonstrate for the first time that expression of IL-10 in lung macrophages stimulated by LPS depends on the concomitant activation of ERK, p38 and JNK MAPKinases, which control downstream signalling to Sp-1 transcription factor. This study further points to Sp-1 as a key signalling pathway for IL-10 expression in the lung.</p

Minutes-duration optical flares with supernova luminosities

In recent years, certain luminous extragalactic optical transients have been observed to last only a few days1. Their short observed duration implies a different powering mechanism from the most common luminous extragalactic transients (supernovae), whose timescale is weeks2. Some short-duration transients, most notably AT2018cow (ref. 3), show blue optical colours and bright radio and X-ray emission4. Several AT2018cow-like transients have shown hints of a long-lived embedded energy source5, such as X-ray variability6,7, prolonged ultraviolet emission8, a tentative X-ray quasiperiodic oscillation9,10 and large energies coupled to fast (but subrelativistic) radio-emitting ejecta11,12. Here we report observations of minutes-duration optical flares in the aftermath of an AT2018cow-like transient, AT2022tsd (the ‘Tasmanian Devil’). The flares occur over a period of months, are highly energetic and are probably nonthermal, implying that they arise from a near-relativistic outflow or jet. Our observations confirm that, in some AT2018cow-like transients, the embedded energy source is a compact object, either a magnetar or an accreting black hole

Tamponade efficiency of perfluorohexyloctane and silicone oil solutions in a model eye chamber

Background/aim: As no single tamponade agent yet fulfils all the requirements of a long term inferior tamponade, attempts have been made to mix tamponade materials. This study investigated perfluorohexyloctane (F(6)H(8)) and silicone oil solutions designed to take advantage of the high specific gravity and interfacial tension of the F(6)H(8) and the high viscosity of silicone oil. Methods: Solutions of three different densities were examined (1.01, 1.03 and 1.06 g/cm(3)) inside transparent chambers made of surface modified poly(methylmethacrylate) (PMMA). Results: Compared to F(6)H(8), the solutions had poorer contact with hydrophilic surface of the chambers. The higher the specific gravity of the solution, the better was the contact. The solution with a specific gravity 1.01 g/cm(3) is probably of no use clinically. Conclusion: The model eye chamber made of surface modified PMMA is an efficient way of screening and choosing solutions with promising physical properties. Solutions of silicone oil with F(6)H(8) in other proportions or with other semifluorinated alkanes may be of interest

Tel/PDGFRβ induces stem cell differentiation via the Ras/ERK and STAT5 signaling pathways

Objective: Fusion genes involving the platelet-derived growth factor receptor-β (PDGFRβ) are found in a subgroup of myeloproliferative neoplasms, with one such fusion, Tel/PDGFRβ found in a subset of chronic myelomonocytic leukemia patients. Tel/PDGFRβ results in constitutive activation of several signaling pathways and induces a myeloproliferative disease in mice, with signals via tyrosines 579/581 identified as being important for this phenotype. In this study, we have used a tetracycline-regulated system to express wild-type and the mutated F2 Tel/PDGFRβ to identify the key signaling pathways, which drive Tel/PDGFRβ-induced differentiation of embryonic stem (ES) cells. Materials and Methods: The leukemic oncogene Tel/PDGFRβ and Tel/PDGFRβ-F2 were inducibly expressed in ES cells and their effects on self-renewal, signal transduction, and gene expression patterns analyzed. Results: Tel/PDGFRβ activated several major signal transduction pathways (signal transducers and activators of transcription [STAT] 3, STAT5, mitogen-activated protein kinases, phosphatidylinositol-3 kinase) in ES cells, but only specific inhibition of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) or STAT5 pathways was able to significantly prevent Tel/PDGFRβ-induced differentiation and restore ES-cell self-renewal. Inhibiting the tyrosine kinase activity of the oncogene using Gleevec or PDGFRβ inhibitor III also substantially prevented Tel/PDGFRβ-induced differentiation and its ability to upregulate key genes involved in myelopoiesis. Tyrosines 579/581 played a critical role in mediating signals via the Ras/ERK and STAT5 pathways, with dual targeting of the tyrosine kinase activity of Tel/PDGFRβ and the MEK/ERK pathway completely preventing Tel/PDGFRβ-induced differentiation. Conclusion: These findings suggest that targeted disruption of key signaling pathways in combination with the tyrosine kinase activity of leukemic oncogenes, such as Tel/PDGFRβ, may result in more efficacious therapies for suppressing leukemic progression in the clinical setting

Teachers’ responses to instances of student mathematical thinking with varied potential to support student learning

Teacher responses to student mathematical thinking (SMT) matter because the way in which teachers respond affects student learning. Although studies have provided important insights into the nature of teacher responses, little is known about the extent to which these responses take into account the potential of the instance of SMT to support learning. This study investigated teachers’ responses to a common set of instances of SMT with varied potential to support students’ mathematical learning, as well as the productivity of such responses. To examine variations in responses in relation to the mathematical potential of the SMT to which they are responding, we coded teacher responses to instances of SMT in a scenario-based interview. We did so using a scheme that analyzes who interacts with the thinking (Actor), what they are given the opportunity to do in those interactions (Action), and how the teacher response relates to the actions and ideas in the contributed SMT (Recognition). The study found that teachers tended to direct responses to the student who had shared the thinking, use a small subset of actions, and explicitly incorporate students’ actions and ideas. To assess the productivity of teacher responses, we first theorized the alignment of different aspects of teacher responses with our vision of responsive teaching. We then used the data to analyze the extent to which specific aspects of teacher responses were more or less productive in particular circumstances. We discuss these circumstances and the implications of the findings for teachers, professional developers, and researchers

Conceptualizing important facets of teacher responses to student mathematical thinking

We argue that progress in the area of research on mathematics teacher responses to student thinking could be enhanced were the field to attend more explicitly to important facets of those responses, as well as to related units of analysis. We describe the Teacher Response Coding scheme (TRC) to illustrate how such attention might play out, and then apply the TRC to an excerpt of classroom mathematics discourse to demonstrate the affordances of this approach. We conclude by making several further observations about the potential versatility and power in articulating units of analysis and developing and applying tools that attend to these facets when conducting research on teacher responses

Using Public Records to Scaffold Joint Sense Making

Teachers can more productively use board work to scaffold joint sense making