Molecular mechanisms underlying the regulation of interleukin-10 production in macrophages

Interleukin (IL)-10 is an immunosuppressive cytokine that plays a crucial role in preventing inflammatory and autoimmune pathology. The dysregulation of IL-10 during infection can lead to either an over-exuberant response damaging the host, or conversely ineffective pathogen clearance. Macrophages are important players in inflammatory responses and produce IL-10 in response to Toll-like receptor (TLR) ligation along with protective pro-inflammatory cytokines. The collective regulation of these cytokines is central to the generation of an effective but balanced immune response. We observed that type I IFN is one factor that leads to differential production of IL-10 and pro-inflammatory cytokines in TLR4 stimulated C57BL/6 and BALB/c macrophages. The effects of type I IFN on pro-inflammatory cytokine production were IL-10 dependent and independent. Hence, we further investigated how type I IFN regulates IL-10 production and showed that type I IFN acts as a transcriptional regulator of Il10 mRNA via activation of ERK1/2, and additionally stabilises Il10 mRNA transcripts in TLR4 stimulated macrophages. Using an assay for transposase-accessible chromatin with high throughput sequencing we further unravelled how type I IFN regulates Il10 transcription. We were able to demonstrate that type I IFN increases chromatin accessibility and augments the recruitment of the transcription factors ATF3 and JUNB to the Il10 locus in macrophages upon LPS stimulation. These findings highlight key pathways responsible for the type I IFN-dependent regulation of IL-10, and may provide valuable information for the development of immunomodulatory treatments of inflammatory diseases

Enhanced activation of an amino-terminally truncated isoform of the voltage-gated proton channel HVCN1 enriched in malignant B cells

The final published version can be found here: http://dx.doi.org/10.1073/pnas.1411390111M.C. is the recipient of a Bennett Fellowship from Leukaemia and Lymphoma Research (ref. 12002). M.A.B. is supported by a GlaxoSmithKline Oncology–Biotechnology and Biological Sciences Research Council Collaborative Awards in Science and Engineering PhD studentship. This work was supported by National Institutes of Health Grants GM087507 and GM102336 (to T.E.D.)

Recombinant DNA technology and click chemistry: a powerful combination for generating a hybrid elastin-like-statherin hydrogel to control calcium phosphate mineralization

Producción CientíficaUnderstanding the mechanisms responsible for generating different phases and morphologies of calcium phosphate by elastin-like recombinamers is supreme for bioengineering of advanced multifunctional materials. The generation of such multifunctional hybrid materials depends on the properties of their counterparts and the way in which they are assembled. The success of this assembly depends on the different approaches used, such as recombinant DNA technology and click chemistry. In the present work, an elastin-like recombinamer bearing lysine amino acids distributed along the recombinamer chain has been cross-linked via Huisgen [2 + 3] cycloaddition. The recombinamer contains the SNA15 peptide domains inspired by salivary statherin, a peptide epitope known to specifically bind to and nucleate calcium phosphate. The benefit of using click chemistry is that the hybrid elastin-like-statherin recombinamers cross-link without losing their fibrillar structure. Mineralization of the resulting hybrid elastin-like-statherin recombinamer hydrogels with calcium phosphate is described. Thus, two different hydroxyapatite morphologies (cauliflower- and plate-like) have been formed. Overall, this study shows that crosslinking elastin-like recombinamers leads to interesting matrix materials for the generation of calcium phosphate composites with potential applications as biomaterials.Ministerio de Economía, Industria y Competitividad (Project MAT2013- 42473-R and MAT2013-41723-R)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA244U13, VA313U14 and GRS/516/A/10

Facile Synthesis of Hierarchical CuS and CuCo2S4 Structures from an Ionic Liquid Precursor for Electrocatalysis Applications

Covellite-phase CuS and carrollite-phase CuCo2S4 nano- and microstructures were synthesized from tetrachloridometallate-based ionic liquid precursors using a novel, facile, and highly controllable hot-injection synthesis strategy. The synthesis parameters including reaction time and temperature were first optimized to produce CuS with a well-controlled and unique morphology, providing the best electrocatalytic activity toward the oxygen evolution reaction (OER). In an extension to this approach, the electrocatalytic activity was further improved by incorporating Co into the CuS synthesis method to yield CuCo2S4 microflowers. Both routes provide high microflower yields of >80 wt %. The CuCo2S4 microflowers exhibit a superior performance for the OER in alkaline medium compared to CuS. This is demonstrated by a lower onset potential (∼1.45 V vs RHE @10 mA/cm2), better durability, and higher turnover frequencies compared to bare CuS flowers or commercial Pt/C and IrO2 electrodes. Likely, this effect is associated with the presence of Co3+ sites on which a better adsorption of reactive species formed during the OER (e.g., OH, O, OOH, etc.) can be achieved, thus reducing the OER charge-transfer resistance, as indicated by X-ray photoelectron spectroscopy and electrochemical impedance spectroscopy measurements

Differential production of type I IFN determines the reciprocal levels of IL-10 and proinflammatory cytokines produced by C57BL/6 and BALB/c macrophages

Pattern recognition receptors detect microbial products and induce cytokines, which shape the immunological response. IL-12, TNF-alpha, and IL-1 beta are proinflammatory cytokines, which are essential for resistance against infection, but when produced at high levels they may contribute to immunopathology. In contrast, IL-10 is an immunosuppressive cytokine, which dampens proinflammatory responses, but it can also lead to defective pathogen clearance. The regulation of these cytokines is therefore central to the generation of an effective but balanced immune response. In this study, we show that macrophages derived from C57BL/6 mice produce low levels of IL-12, TNF-alpha, and IL-1 beta, but high levels of IL-10, in response to TLR4 and TLR2 ligands LPS and Pam3CSK4, as well as Burkholderia pseudomallei, a Gram-negative bacterium that activates TLR2/4. In contrast, macrophages derived from BALB/c mice show a reciprocal pattern of cytokine production. Differential production of IL-10 in B. pseudomallei and LPS-stimulated C57BL/6 and BALB/c macrophages was due to a type I IFN and ERK1/2-dependent, but IL-27-independent, mechanism. Enhanced type I IFN expression in LPS-stimulated C57BL/6 macrophages was accompanied by increased STAT1 and IFN regulatory factor 3 activation. Furthermore, type I IFN contributed to differential IL-1 beta and IL-12 production in B. pseudomallei and LPS-stimulated C57BL/6 and BALB/c macrophages via both IL-10-dependent and -independent mechanisms. These findings highlight key pathways responsible for the regulation of pro- and anti-inflammatory cytokines in macrophages and reveal how they may differ according to the genetic background of the host.his work was supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001126), the U.K. Medical Research Council (FC001126), and the Wellcome Trust (FC001126) since April 1, 2015 and before that by U.K. Medical Research Council Grant MRC U117565642 and also by European Research Council Grant 294682-TB-PATH (Crick 10127). A.H. was additionally funded by a U.K. Medical Research Council Centenary Award. M.S. was funded by Fundação para a Ciência e Tecnologia, Portugal Grant FCT-ANR/BIM-MEC/ 0007/2013. M.S. is an associate Fundação para a Ciência e Tecnologia, Portugal investigator.info:eu-repo/semantics/publishedVersio

5-teilige Sonderausgabe des KOBV-Newsletters – 24. bis 30. Oktober 2016

An der internationalen Open-Access-Woche 2016 vom 24.-28. Oktober war der KOBV erstmalig mit einem Online „Publishing Event“ beteiligt. An fünf aufeinanderfolgenden Tagen erschien täglich eine Sonderausgabe des KOBV- Newsletters zu ausgewählten Open-Access-Themen. Die einzelnen Beiträge sind in dieser Sonderedition als Online-Reader zusammengestellt. Der aktuelle Diskussionsstand zum jeweiligen Thema wird von Expertinnen und Experten in kurzen Übersichtsartikeln vorgestellt und mit Praxistipps ergänzt. Zielgruppe sind vor allem Bibliothekare und Bibliothekarinnen, die sich einen schnellen Überblick zu Open Access verschaffen wollen

Disinfection of water with new chitosan-modified hybrid clay composite adsorbent

Hybrid clay composites were prepared from Kaolinite clay and Carica papaya seeds via modification with chitosan, Alum, NaOH, and ZnCl2 in different ratios, using solvothermal and surface modification techniques. Several composite adsorbents were prepared, and the most efficient of them for the removal of gram negative enteric bacteria was the hybrid clay composite that was surface-modified with chitosan, Ch-nHYCA1:5 (Chitosan: nHYCA = 1:5). This composite adsorbent had a maximum adsorption removal value of 4.07 × 106 cfu/mL for V. cholerae after 120 min, 1.95 × 106 cfu/mL for E. coli after ∼180 min and 3.25 × 106 cfu/mL for S. typhi after 270 min. The Brouers-Sotolongo model was found to better predict the maximum adsorption capacity (qmax) of Ch-nHYCA1:5 composite adsorbent for the removal of E. coli with a qmax of 103.07 mg/g (7.93 × 107 cfu/mL) and V. cholerae with a qmax of 154.18 mg/g (1.19 × 108 cfu/mL) while the Sips model best described S. typhi adsorption by Ch-nHYCA1:5 composite with an estimated qmax of 83.65 mg/g (6.43 × 107 cfu/mL). These efficiencies do far exceed the alert/action levels of ca. 500 cfu/mL in drinking water for these bacteria. The simplicity of the composite preparation process and the availability of raw materials used for its preparation underscore the potential of this low-cost chitosan-modified composite adsorbent (Ch-nHYCA1:5) for water treatment

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin