In vivo analysis of the evolutionary conserved BTD-box domain of Sp1 and Btd during Drosophila development.

The Sp family of transcription factors plays important functions during development and disease. An evolutionary conserved role for some Sp family members is the control of limb development. The family is characterized by the presence of three C2H2-type zinc fingers and an adjacent 10 aa region with an unknown function called the Buttonhead (BTD) box. The presence of this BTD-box in all Sp family members identified from arthropods to vertebrates, suggests that it plays an essential role during development. However, despite its conservation, the in vivo function of the BTD-box has never been studied. In this work, we have generated specific BTD-box deletion alleles for the Drosophila Sp family members Sp1 and buttonhead (btd) using gene editing tools and analyzed its role during development. Unexpectedly, btd and Sp1 mutant alleles that lack the BTD-box are viable and have almost normal appendages. However, in a sensitized background the requirement of this domain to fully regulate some of Sp1 and Btd target genes is revealed. Furthermore, we have also identified a novel Sp1 role promoting leg vs antenna identity through the repression of spineless (ss) expression in the leg, a function that also depends on the Sp1 BTD-box.

CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs.

CD137 (4-1BB, Tnsfr9) is a member of the TNF-receptor (TNFR) superfamily without known intrinsic enzymatic activity in its cytoplasmic domain. Hence, akin to other members of the TNFR family, it relies on the TNFR-Associated-Factor (TRAF) family of adaptor proteins to build the CD137 signalosome for transducing signals into the cell. Thus, upon CD137 activation by binding of CD137L trimers or by crosslinking with agonist monoclonal antibodies, TRAF1, TRAF2, and TRAF3 are readily recruited to the cytoplasmic domain of CD137, likely as homo- and/or heterotrimers with different configurations, initiating the construction of the CD137 signalosome. The formation of TRAF2-RING dimers between TRAF2 molecules from contiguous trimers would help to establish a multimeric structure of TRAF-trimers that is probably essential for CD137 signaling. In addition, available studies have identified a large number of proteins that are recruited to CD137:TRAF complexes including ubiquitin ligases and proteases, kinases, and modulatory proteins. Working in a coordinated fashion, these CD137-signalosomes will ultimately promote CD137-mediated T cell proliferation and survival and will endow T cells with stronger effector functions. Current evidence allows to envision the molecular events that might take place in the early stages of CD137-signalosome formation, underscoring the key roles of TRAFs and of K63 and K48-ubiquitination of target proteins in the signaling process. Understanding the composition and fine regulation of CD137-signalosomes assembly and disassembly will be key to improve the therapeutic activities of chimeric antigen receptors (CARs) encompassing the CD137 cytoplasmic domain and a new generation of CD137 agonists for the treatment of cancer.

Optimization of techniques for the extinction and prevention of coal fires produced in final walls as a result of spontaneous combustion in the Cerrejón mine-Colombia.

The Cerrejón mine has identified fires in its coal production seams for a few years in its operation. Fires are produced as a result of spontaneous combustion phenomena. Coal spontaneous combustion is a phenomenon that occurs naturally during coal oxidation when exposed to atmospheric conditions, due to erosion processes, geological and mining practices. This phenomenon is a subject of great concern in the world's coal mines, as it causes environmental problems, generating emissions of polluting gases into the atmosphere and economic losses due to reserve consumption. In this work, we seek to optimize the prevention and extinction processes used by the company. In terms of prevention, the current state was evaluated and alternatives, such as diluted bitumen and brine (combustion inhibitor), cement/slaked lime, fine sand cement, and clinker/slaked lime were developed to avoid ignition. As far as extinction is concerned, an additional methodology for medium magnitude fires was determined, in order to improve extinction times through the use of cooling. It was determined that the bitumen/brine has better adhesion and durability properties in the coal seam. Extinction through reagent cooling is quicker, thus improving the backhoe's productivity and minimizing costs.

Persistently elevated exhaled nitric oxide fraction is associated with increased risk of exacerbation in COPD.

Preventing the occurrence of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a major therapeutic goal. We hypothesise that persistently increased levels of exhaled nitric oxide (FeNO) during follow-up can identify a group of COPD patients at higher risk of AECOPD.To test this hypothesis, we measured FeNO levels (HypAir FeNO®, Medisoft; Sorinnes, Belgium) prospectively in 226 clinically stable COPD outpatients at recruitment and during follow-up (at 6 and 12 months). Patients were stratified according to the number of visits with FeNO ≥20 ppb.FeNO was <20 ppb in all three visits in 44.2% of patients, 29.6% in visit 1 and 26.1% in visit 2 or 3. These three groups suffered progressively higher AECOPD rates during follow-up (0.67, 0.91 and 1.42, respectively, p<0.001). After adjusting for potential confounding variables (log-rank test), the hazard ratio for AECOPD was higher in the latter group (1.579 (95% CI 1.049-2.378), p=0.029). Likewise, time to first moderate and severe AECOPD was shorter in these patients. Finally, there was no relationship between FeNO levels and circulating eosinophils.Persistent FeNO levels ≥20 ppb in clinically stable COPD outpatients are associated with a significantly higher risk of AECOPD.