Química Supramolecular amb Jean-Marie Lehn

"La química supramolecular pot ajudar a fer medicaments més eficaços". Amb motiu de les II Jornades Doctorals organitzades el passat juny des del Departament de Química de la UAB, el Premi Nobel de Química de l'any 1987 Jean-Marie Lehn va visitar la nostra universitat per impartir una xerrada sobre el disseny de nanoestructures supramoleculars i les seves aplicacions. Aprofitant aquesta visita, des d'UAB Divulga li vam realitzar una entrevista per saber més coses sobre la química supramolecular, els límits entre la vida i la no-vida i l'impacte de rebre el Premi Nobel.Con motivo de las II Jornadas Doctorales organizadas el pasado junio desde el Departamento de Química de la UAB, el Premio Nobel de Química del año 1987 Jean-Marie Lehn visitó nuestra universidad para impartir una conferencia sobre el diseño de nanoestructuras supramoleculares y sus aplicaciones. Aprovechando esta visita, desde UAB Divulga le realizamos una entrevista para saber más sobre la química supramolecular, los límites entre la vida y la no-vida y el impacto de recibir el Premio Nobel.On the occasion of the II Doctoral Seminars, organised by the UAB Department of Chemistry, Nobel Laureate Jean-Marie Lehn, who received the Nobel Prize in Chemistry 1987, visited our university to give a speech on the design of supramolecular nanostructures and their applications. Taking advantage of his visit, UABDivulga interviewed him to learn more about supramolecular chemistry, the boundaries between life and non-life and the impact of receiving the Nobel Prize

Novel E3 Ubiquitin Ligases That Regulate Histone Protein Levels in the Budding Yeast Saccharomyces cerevisiae

Core histone proteins are essential for packaging the genomic DNA into chromatin in all eukaryotes. Since multiple genes encode these histone proteins, there is potential for generating more histones than what is required for chromatin assembly. The positively charged histones have a very high affinity for negatively charged molecules such as DNA, and any excess of histone proteins results in deleterious effects on genomic stability and cell viability. Hence, histone levels are known to be tightly regulated via transcriptional, posttranscriptional and posttranslational mechanisms. We have previously elucidated the posttranslational regulation of histone protein levels by the ubiquitin-proteasome pathway involving the E2 ubiquitin conjugating enzymes Ubc4/5 and the HECT (Homologous to E6-AP C-Terminus) domain containing E3 ligase Tom1 in the budding yeast. Here we report the identification of four additional E3 ligases containing the RING (Really Interesting New Gene) finger domains that are involved in the ubiquitylation and subsequent degradation of excess histones in yeast. These E3 ligases are Pep5, Snt2 as well as two previously uncharacterized Open Reading Frames (ORFs) YKR017C and YDR266C that we have named Hel1 and Hel2 (for Histone E3 Ligases) respectively. Mutants lacking these E3 ligases are sensitive to histone overexpression as they fail to degrade excess histones and accumulate high levels of endogenous histones on histone chaperones. Co-immunoprecipitation assays showed that these E3 ligases interact with the major E2 enzyme Ubc4 that is involved in the degradation related ubiquitylation of histones. Using mutagenesis we further demonstrate that the RING domains of Hel1, Hel2 and Snt2 are required for histone regulation. Lastly, mutants corresponding to Hel1, Hel2 and Pep5 are sensitive to replication inhibitors. Overall, our results highlight the importance of posttranslational histone regulatory mechanisms that employ multiple E3 ubiquitin ligases to ensure excess histone degradation and thus contribute to the maintenance of genomic stability

How Fire History, Fire Suppression Practices and Climate Change Affect Wildfire Regimes in Mediterranean Landscapes

Available data show that future changes in global change drivers may lead to an increasing impact of fires on terrestrial ecosystems worldwide. Yet, fire regime changes in highly humanised fire-prone regions are difficult to predict because fire effects may be heavily mediated by human activities We investigated the role of fire suppression strategies in synergy with climate change on the resulting fire regimes in Catalonia (north-eastern Spain). We used a spatially-explicit fire-succession model at the landscape level to test whether the use of different firefighting opportunities related to observed reductions in fire spread rates and effective fire sizes, and hence changes in the fire regime. We calibrated this model with data from a period with weak firefighting and later assess the potential for suppression strategies to modify fire regimes expected under different levels of climate change. When comparing simulations with observed fire statistics from an eleven-year period with firefighting strategies in place, our results showed that, at least in two of the three sub-regions analysed, the observed fire regime could not be reproduced unless taking into account the effects of fire suppression. Fire regime descriptors were highly dependent on climate change scenarios, with a general trend, under baseline scenarios without fire suppression, to large-scale increases in area burnt. Fire suppression strategies had a strong capacity to compensate for climate change effects. However, strong active fire suppression was necessary to accomplish such compensation, while more opportunistic fire suppression strategies derived from recent fire history only had a variable, but generally weak, potential for compensation of enhanced fire impacts under climate change. The concept of fire regime in the Mediterranean is probably better interpreted as a highly dynamic process in which the main determinants of fire are rapidly modified by changes in landscape, climate and socioeconomic factors such as fire suppression strategies

A C2HC zinc finger is essential for the RING-E2 interaction of the ubiquitin ligase RNF125

The activity of RING ubiquitin ligases (E3s) depends on an interaction between the RING domain and ubiquitin conjugating enzymes (E2), but posttranslational events or additional structural elements, yet largely undefined, are frequently required to enhance or regulate activity. Here, we show for the ubiquitin ligase RNF125 that, in addition to the RING domain, a C2HC Zn finger (ZnF) is crucial for activity, and a short linker sequence (Li2(120-128)) enhances activity. The contribution of these regions was first shown with truncated proteins, and the essential role of the ZnF was confirmed with mutations at the Zn chelating Cys residues. Using NMR, we established that the C2HC ZnF/Li2(120-128) region is crucial for binding of the RING domain to the E2 UbcH5a. The partial X-ray structure of RNF125 revealed the presence of extensive intramolecular interactions between the RING and C2HC ZnF. A mutation at one of the contact residues in the C2HC ZnF, a highly conserved M112, resulted in the loss of ubiquitin ligase activity. Thus, we identified the structural basis for an essential role of the C2HC ZnF and conclude that this domain stabilizes the RING domain, and is therefore required for binding of RNF125 to an E2

Machine learning approaches identify chemical features for stage-specific antimalarial compounds

DATA AVAILABILITY STATEMENT : Code Availability Statement: All python scripts for clustering, undersampling and model building as well as evaluation can be obtained from github: http://github.com/M2PL/Machines- Against-Malaria. To facilitate model usage, we have also incorporated the models in the Ersilia Model Hub (https:// www.ersilia.io/model-hub; identifier eos80ch).SUPPORTING INFORMATION : Information on hyperparameters used for model building and additional performance metrics of model predictions in representative and novel chemical spaces (PDF) Chemical information on compounds within the databases used for ML as well as performance metrics of models trained on imbalanced/oversampled/undersampled data using either ECFP or MACCS molecular fingerprints as well as information on enriched ECFP features for activity/inactivity against ABS and/or gametocytes. SMILES contains Simplified Molecular Input Line Entry System (SMILES) of compounds used for machine learning.Efficacy data from diverse chemical libraries, screened against the various stages of the malaria parasite Plasmodium falciparum, including asexual blood stage (ABS) parasites and transmissible gametocytes, serve as a valuable reservoir of information on the chemical space of compounds that are either active (or not) against the parasite. We postulated that this data can be mined to define chemical features associated with the sole ABS activity and/or those that provide additional life cycle activity profiles like gametocytocidal activity. Additionally, this information could provide chemical features associated with inactive compounds, which could eliminate any future unnecessary screening of similar chemical analogs. Therefore, we aimed to use machine learning to identify the chemical space associated with stage-specific antimalarial activity. We collected data from various chemical libraries that were screened against the asexual (126 374 compounds) and sexual (gametocyte) stages of the parasite (93 941 compounds), calculated the compounds’ molecular fingerprints, and trained machine learning models to recognize stage-specific active and inactive compounds. We were able to build several models that predict compound activity against ABS and dual activity against ABS and gametocytes, with Support Vector Machines (SVM) showing superior abilities with high recall (90 and 66%) and low false-positive predictions (15 and 1%). This allowed the identification of chemical features enriched in active and inactive populations, an important outcome that could be mined for essential chemical features to streamline hit-to-lead optimization strategies of antimalarial candidates. The predictive capabilities of the models held true in diverse chemical spaces, indicating that the ML models are therefore robust and can serve as a prioritization tool to drive and guide phenotypic screening and medicinal chemistry programs.The South African Department of Science and Innovation and National Research Foundation South African Research Chairs Initiative.http://pubs.acs.org/journal/acsodfam2024BiochemistryGeneticsMicrobiology and Plant PathologyPhysiologyUP Centre for Sustainable Malaria Control (UP CSMC)SDG-03:Good heatlh and well-bein

Identifying priorities for the protection of deep Mediterranean Sea ecosystems through an integrated approach

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Fanelli, E., Bianchelli, S., Foglini, F., Canals, M., Castellan, G., Guell-Bujons, Q., Galil, B., Goren, M., Evans, J., Fabri, M.-C., Vaz, S., Ciuffardi, T., Schembri, P. J., Angeletti, L., Taviani, M., & Danovaro, R. Identifying priorities for the protection of deep Mediterranean Sea ecosystems through an integrated approach. Frontiers in Marine Science, 8, (2021): 698890, https://doi.org/10.3389/fmars.2021.698890.Benthic habitats of the deep Mediterranean Sea and the biodiversity they host are increasingly jeopardized by increasing human pressures, both direct and indirect, which encompass fisheries, chemical and acoustic pollution, littering, oil and gas exploration and production and marine infrastructures (i.e., cable and pipeline laying), and bioprospecting. To this, is added the pervasive and growing effects of human-induced perturbations of the climate system. International frameworks provide foundations for the protection of deep-sea ecosystems, but the lack of standardized criteria for the identification of areas deserving protection, insufficient legislative instruments and poor implementation hinder an efficient set up in practical terms. Here, we discuss the international legal frameworks and management measures in relation to the status of habitats and key species in the deep Mediterranean Basin. By comparing the results of a multi-criteria decision analysis (MCDA) and of expert evaluation (EE), we identify priority deep-sea areas for conservation and select five criteria for the designation of future protected areas in the deep Mediterranean Sea. Our results indicate that areas (1) with high ecological relevance (e.g., hosting endemic and locally endangered species and rare habitats),(2) ensuring shelf-slope connectivity (e.g., submarine canyons), and (3) subject to current and foreseeable intense anthropogenic impacts, should be prioritized for conservation. The results presented here provide an ecosystem-based conservation strategy for designating priority areas for protection in the deep Mediterranean Sea.This study was supported by the DG ENV project IDEM (Implementation of the MSFD to the Deep Mediterranean Sea; contract EU No. 11.0661/2017/750680/SUB/EN V.C2). MC and QG-B acknowledge support from Generalitat de Catalunya autonomous government through its funding scheme to excellence research groups (Grant 2017 SGR 315)

Iohexol degradation in wastewater and urine by UV-based Advanced Oxidation Processes (AOPs): Process modeling and by-products identification

In this work, an Iodinated Contrast Medium (ICM), Iohexol, was subjected to treatment by 3 Advanced Oxidation Processes (AOPs) (UV, UV/H2O2, UV/H2O2/Fe2+). Water, wastewater and urine were spiked with Iohexol, in order to investigate the treatment efficiency of AOPs. A tri-level approach has been deployed to assess the UV-based AOPs efficacy. The treatment was heavily influenced by the UV transmittance and the organics content of the matrix, as dilution and acidification improved the degradation but iron/H2O2 increase only moderately. Furthermore, optimization of the treatment conditions, as well as modeling of the degradation was performed, by step-wise constructed quadratic or product models, and determination of the optimal operational regions was achieved through desirability functions. Finally, global chemical parameters (COD, TOC and UV-Vis absorbance) were followed in parallel with specific analyses to elucidate the degradation process of Iohexol by UV-based AOPs. Through HPLC/MS analysis the degradation pathway and the effects the operational parameters were monitored, thus attributing the pathways the respective modifications. The addition of iron in the UV/H2O2 process inflicted additional pathways beneficial for both Iohexol and organics removal from the matrix