Copper-Catalyzed Dehydrogenative Amidation of Light Alkanes

The functionalization of C-H bonds in light alkanes, particularly to form C-N bonds, remains a challenge. We report the dehydrogenative coupling of amides with C1–C4 hydrocarbons to form N-alkyl amide products with tBuOOtBu as oxidant, and a copper complex of a phenanthroline-type ligand as catalyst. The reactions occurred in good yields in benzene or supercritical carbon dioxide as solvents. This strategy allowed for the determination of the relative reactivity of these alkane C-H bonds toward this amination process and showed, in contrast to prior work with larger alkanes, that the reactivity correlated with bond dissociation energies.Support for this work was provided by the MINECO (CTQ2017-82893-C2-1-R), Junta de Andalucía (P18-RT-1536) and PO FEDER 2014–2020 (UHU-1260216). Work at UCB was supported by the Director, Office of Science, of the US Department of Energy under contract no. DE-AC02- 05CH11231. M.A.F. thanks MINECO for a Juan de la Cierva Incorporación fellowship. Funding for open access charges is given by Universidad de Huelva/ CBUA

Intermetallic coinage metal-catalyzed functionalization of alkanes with ethyl diazoacetate : gold as a ligand

The complexes [Au2M2(C6F5)4(NCMe)2]n (M = Cu, 1; M = Ag, 2) have been tested as catalysts for the functionalization of alkanes by the carbene insertion methodology, using ethyl diazoacetate as the carbene source. Moderate to high conversions have been obtained. The observed selectivities seem to favor the proposal that the active metal for catalysis is the Cu/Ag center, the Au(C6F5)2 unit acting as a spectator ligand in both cases.DGI for funding (CTQ2008-00042/BQU and CTQ2010-20500-C02-02

TLR7 activation in M-CSF-dependent monocyte-derived human macrophages potentiates inflammatory responses and prompts neutrophil recruitment

1 p.-4 fig.Toll-like receptor 7 (TLR7) is an endosomal Pathogen-Associated Molecular Pattern (PAMP) receptor that senses single-stranded RNA (ssRNA) and whose engagement results in the production of type I IFN and pro-inflammatory cytokines upon viral exposure. Recent genetic studies have established that a dysfunctional TLR7-initiated signaling is directly linked to the development of SARS-CoV-2-induced severe COVID-19. We previously showed that TLR7 is preferentially expressed by macrophages generated in the presence of M-CSF (M-MØ), whose MAFB-dependent transcriptome resembles pathogenic pulmonary monocyte-derived macrophage subsets in severe COVID-19. We now report that TLR7 activation in M-MØ triggers a weak MAPK, NFkB and STAT1 activation and leads to defective production of type I IFN. Nonetheless, TLR7 engagement re-programs MAFB+ M-MØ towards a distinctive transcriptional profile. Specifically, TLR7-activated M-MØ acquired the expression of genes that characterize inflammatory macrophage subsets in COVID-19 and other inflammatory diseases, including genes encoding neutrophil-attracting chemokines (CXCL1-3, CXCL5, CXCL8) reported as biomarkers for severe COVID-19. Functionally, TLR7-activated M-MØ displayed enhanced proinflammatory responses towards secondary stimulation and a robust production of neutrophil-attracting chemokines (CXCL1, CXCL5, CXCL8), which was dependent on the transcription factors MAFB and AhR. Interestingly, CXCL1 and CXCL5 release from M-MØ was also promoted by SARS-CoV-2 but not by Virus-like particles. As defective TLR7 signaling and enhanced pulmonary neutrophil/lymphocyte ratio associate with severe COVID-19, these results suggest that targeting macrophage TLR7 might be a therapeutic strategy for viral infections where monocyte-derived macrophages exhibit a pathogenic role.This research work was also funded by the European Commission – NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global)Peer reviewe

Assessment of the influence of direct tobacco smoke on infection and active TB management

Smoking is a risk factor for tuberculosis (TB) infection and disease progression. Tobacco smoking increases susceptibility to TB in a variety of ways, one of which is due to a reduction of the IFN-γ response. Consequently, an impaired immune response could affect performance of IFN-γ Release Assays (IGRAs).Miguel Servet program of the Instituto de Salud Carlos III (Spain). ML was supported by a joint ERS/SEPAR fellowship (LTRF 2015). The research was partially supported by a grant from the Instituto de Salud Carlos III (PI 13/01546 and PI 16/01912), integrated in the Plan Nacional de I+D+I and cofunded by the ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); and a grant from the Sociedad Española de Neumología y Cirugía Torácica (SEPAR; Barcelona, Spain) (Smoking Integrated Research Programme Call) to NA

The GSK3b-MAFB axis controls the pro-fibrotic gene profile of pathogenic monocyte-derived macrophages in severe COVID-19

1 p.-4 fig.MAF and MAFB are members of the “large MAF” transcription factor family that shape the transcriptome of antiinflammatory and pro-tumoral human macrophages. We have now determined the MAF- and MAFB-dependent gene profile of M-CSF-dependent monocyte-derived macrophages (M-MØ), and found that both factors exhibit overlapping transcriptional outcomes during monocyte-to-M-MØ differentiation, but differentially affect macrophage effector functions like production of monocyte-recruiting chemokines, T-cell activation and immunosuppression. Remarkably, MAFB was found to positively regulate the expression of the genesets that define the pathogenic monocyte-derived pulmonary macrophage subsets in COVID-19, as evidenced through siRNA-mediated silencing and analysis of MAFBoverexpressing M-MØ from a Multicentric Carpotarsal Osteolysis (MCTO) patient. MAFB silencing downregulated theexpression of genes coding for biomarkers of COVID-19 severity, and genome-wide mapping of MAFB-binding elements in M-MØ identified biomarkers of COVID-19 severity (CD163, IL10, HGF and CCL2) as direct MAFB targets. Further, and in line with the GSK3b-dependent expression of MAFB, GSK3b inhibition in M-MØ significantly boosted the expression of genes that characterize pathogenic macrophage subsets in severe COVID-19, an effect that was primarily dependent on MAFB. In addition, we have demonstrated that a large number of MAFB-dependent genes, as well as GSK3b-dependent expression of MAFB genes were modulated by SARS-Cov-2 infection on human macrophages. Globally, our results demonstrate that the GSK3b-MAFB axis controls the transcriptome of pathogenic pulmonary macrophages in COVID-19,and positively regulates the expression of biomarkers for COVID-19 severity. Thus, macrophage re-programming through modulation of GSK3 -MAFB axis has potential therapeutic strategy for COVID-19 and other inflammatory diseases.This research work was also funded by the European Commission– NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global).Peer reviewe

Development and Evaluation of an NTM-IGRA to Guide Pediatric Lymphadenitis Diagnosis

Background: Diagnosis of nontuberculous mycobacteria (NTM) infections remains a challenge. In this study, we describe the evaluation of an immunological NTM-interferon (IFN)-γ release assay (IGRA) that we developed using glycopeptidolipids (GPLs) as NTM-specific antigens. Methods: We tested the NTM-IGRA in 99 samples from pediatric patients. Seventy-five were patients with lymphadenitis: 25 were NTM confirmed, 45 were of unknown etiology but compatible with mycobacterial infection and 5 had lymphadenitis caused by an etiologic agent other than NTM. The remaining 24 samples were from control individuals without lymphadenitis (latently infected with M.Tuberculosis, uninfected controls and active tuberculosis patients). Peripheral blood mononuclear cells were stimulated overnight with GPLs. Detection of IFN-γ producing cells was evaluated by enzyme-linked immunospot assay. Results: NTM culture-confirmed lymphadenitis patient samples had a significantly higher response to GPLs than the patients with lymphadenitis of unknown etiology but compatible with mycobacterial infection (P < 0.001) and lymphadenitis not caused by NTM (P < 0.01). We analyzed the response against GPLs in samples from unknown etiology lymphadenitis but compatible with mycobacterial infection cases according to the tuberculin skin test (TST) response, and although not statistically significant, those with a TST ≥5 mm had a higher response to GPLs when compared with the TST <5 mm group. Conclusions: Stimulation with GPLs yielded promising results in detecting NTM infection in pediatric patients with lymphadenitis. Our results indicate that the test could be useful to guide the diagnosis of pediatric lymphadenitis. This new NTM-IGRA could improve the clinical handling of NTM-infected patients and avoid unnecessary misdiagnosis and treatments

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

MAFB and MAF Transcription Factors as Macrophage Checkpoints for COVID-19 Severity

Defective IFN production and exacerbated inflammatory and pro-fibrotic responses are hallmarks of SARS-CoV-2 infection in severe COVID-19. Based on these hallmarks, and considering the pivotal role of macrophages in COVID-19 pathogenesis, we hypothesize that the transcription factors MAFB and MAF critically contribute to COVID-19 progression by shaping the response of macrophages to SARS-CoV-2. Our proposal stems from the recent identification of pathogenic lung macrophage subsets in severe COVID-19, and takes into consideration the previously reported ability of MAFB to dampen IFN type I production, as well as the critical role of MAFB and MAF in the acquisition and maintenance of the transcriptional signature of M-CSF–conditioned human macrophages. Solid evidences are presented that link overexpression of MAFB and silencing of MAF expression with clinical and biological features of severe COVID-19. As a whole, we propose that a high MAFB/MAF expression ratio in lung macrophages could serve as an accurate diagnostic tool for COVID-19 progression. Indeed, reversing the macrophage MAFB/MAF expression ratio might impair the exacerbated inflammatory and profibrotic responses, and restore the defective IFN type I production, thus becoming a potential strategy to limit severity of COVID-19.This work was supported by grants from Consejo Superior de Investigaciónes Cientı́ficas (202020E228), Ministerio de Economıa y Competitividad (SAF2017-83785-R), and AYUDAS ́ FUNDACIÓ N BBVA A EQUIPOS DE INVESTIGACIÓ N CIENTIFICA SARS-CoV-2 y COVID-19 to MV and AC, Grant ́ 201619.31 from Fundación La Marató/TV3 to AC, and Red de Investigación en Enfermedades Reumáticas (RIER, RD16/0012/ 0007) from Instituto de Salud Carlos III and cofinanced by the European Regional Development Fund “A way to achieve Europe” (ERDF). We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

La cultura extremeña en los materiales curriculares. Juegos populares extremeños

El objetivo del trabajo es el estudio de la cultura extremeña, la realidad histórica y social, y sus recursos. Se estudió el Museo etnográfico y textil de Plasencia, el Parque Natural de Monfragüe, el Valle del Jerte. Se visitaron los lugares indicados, se recopilaron y estudiaron los materiales obtenidos; posteriormente se repartieron las tareas entre los autores formando grupos más pequeños de trabajo.ExtremaduraES

La Cultura Extremeña en los materiales curriculares

Diseño de una página web con contenidos de cultura extremeña. La página recoge información sobre el Valle del Jerte, la dehesa extremeña, los oficios antiguos y sobre cuatro museos extremeños: el Museo Nacional de Arte Romano en Mérida, el Museo Pérez Enciso en Plasencia, el Museo González Santana en Olivenza y el Museo Vostell en Malpartida de Cáceres.ExtremaduraES