Spektroskopische Eigenschaften eines biologisch‐relevanten [Fe2(μ‐O)2] Diamond‐Core‐Motivs mit einem kurzen Eisen‐Eisen‐Abstand

Dieisen-Kofaktoren in Enzymen vollziehen diverse anspruchsvolle Transformationen. Die Strukturen hoch-valenter Intermediate (Q in der löslichen Methanmonooxygenase und X in der Ribonukleotidreduktase) sind Gegenstand aktueller Diskussionen, seit Fe-Fe-Abstände von 2.1–3.4 Å eine Zuordnung zu geöffneten und geschlossen Kernen mit verbrückenden oder terminalen Oxido-Gruppen in den aktiven Zentren ermöglichen. In dieser Studie berichten wir die kristallografische und spektroskopische Charakterisierung eines FeIII2(μ-O)2-Komplexes (2) mit tetraedrischen (4C) Zentren sowie einem geringen Fe-Fe-Abstand (2.52 Å), der in Lösungsmitteln beständig ist. 2 zeigt eine große Fe-K-Vorkanten-Intensität. Diese resultiert aus der starken Asymmetrie an den TD-FeIII-Zentren bedingt durch die kurzen Fe-μ-O-Bindungen. Während ein Fe-Fe-Abstand von ≈2.5 Å für sechsfach-koordinierte Zentren in Q und X unwahrscheinlich ist, könnte ein Fe2(μ-O)2-Kern mit vierfacher (oder möglicherweise auch fünffacher) Koordination flexibel genug sein, um eine kurze Fe-Fe-Separierung mit großer Vorkanten-Intensität zu ermöglichen. Diese Erkenntnis kann dazu beitragen, dass weitere Modelle für die Strukturen der hoch-valenten Dieisen-Intermediate, die sich im Zuge der biologischen O2-Aktivierung bilden, in Betracht gezogen werden.Peer Reviewe

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Understanding C-H oxidation and amination reactions performed by late first-row transition metals: trapping high-valent metal-O/N species

The transformation of C-H bonds into C-O/N bonds is a process of interest in organic synthesis, but controlling the reactivity and selectivity among the multiple C-H bonds existing in most molecules is a challenging task. Traditional methodologies usually rely on the use of stoichiometric reagents that generate important amounts of toxic waste and relatively harsh reaction conditions are required. An alternative to these traditional methods is the use of catalysts, which enable the performance of these transformations under mild conditions, with improved selectivities and using less hazardous reagents. However, finding good catalysts inevitably means that intimate details about the reaction mechanism need to be unraveled. One key issue to further develop more effective catalysts is to understand the mechanism. Thus, this doctoral dissertation is focused on obtaining mechanistic insight into these transformations by trapping the active species that is the high-valent metal-oxygen/nitrogen species based on late first-row transition metalsLa transformació d'enllaços C-H en enllaços C-N/O és un procés interessant en síntesi orgànica, però encara és un repte controlar la reactivitat i selectivitat entre els diferents enllaços C-H presents en les molècules. Les metodologies tradicionals solen estar basades en l'ús de reactius en quantitats estequiomètriques, generant importants quantitats de residus tòxics, i en condicions de reacció agressives. Una alternativa és l'ús de catalitzadors, els quals permeten dur a terme aquestes transformacions en condicions de reacció més suaus, millorant les selectivitats, i utilitzant reactius menys perillosos. No obstant, trobar nous catalitzadors implica conèixer en detall el mecanisme de les reaccions. Per això, aquesta tesi té com a objectiu estudiar els mecanismes d’aquestes transformacions a través de la detecció i estudi de les espècies actives, corresponents a compostos metall-oxigen o metall-nitrogen en alt estat d’oxidació basats en metalls de la primera sèrie de transici

Rapid hydrogen and oxygen atom transfer by a high-valent nickel-oxygen species

Terminal high-valent metal-oxygen species are key reaction intermediates in the catalytic cycle of both enzymes (e.g., oxygenases) and synthetic oxidation catalysts. While tremendous efforts have been directed towards the characterization of the biologically relevant terminal manganese-oxygen and iron-oxygen species, the corresponding analogues based on late-transition metals such as cobalt, nickel or copper are relatively scarce. This is in part related to the “Oxo Wall” concept, which predicts that late transition elements cannot support a terminal oxido ligand in a tetragonal environment. Here, the nickel(II) complex (1) of the tetradentate macrocyclic ligand bearing a 2,6-pyridinedicarboxamidate unit is shown to be an effective catalyst in the chlorination and oxidation of C-H bonds with sodium hypochlorite as terminal oxidant in the presence of acetic acid (AcOH). Insight into the active species responsible for the observed reactivity was gained through the study of the reaction of 1 with ClO- at low temperature by UV/Vis absorption, resonance Raman, EPR, ESI-MS, and XAS analyses. DFT calculations aided the assignment of the trapped chromophoric species (3) as a nickel-hypochlorite species. Despite the fact that the formal oxidation state of the nickel in 3 is +4, experimental and computational analysis indicate that 3 is best formulated as a NiIII complex with one unpaired electron delocalized in the ligands surrounding the metal center. Most remarkably, 3 reacts rapidly with a range of substrates including those with strong aliphatic C-H bonds, indicating the direct involvement of 3 in the oxidation/chlorination reactions observed in the 1/ClO-/AcOH catalytic systemFinancial support for this work was provided by the European Commission (FP7-PEOPLE- 2011-CIG-303522 to A.C.). The MINECO of Spain is acknowledged for a Ramón y Cajal contract to A.C. and for CTQ2013-43012-P to A.C. F. A.-P. thanks Universitat de Girona for a predoctoral grant. W.R.B. acknowledges the European Research Council (ERC-2011-StG- 279549) and the Ministry of Education, Culture and Science (Gravity program 024.001.035). Xray absorption data was collected on beamline BM25-Spline at the European Synchrotron Radiation Facility (ESRF), Grenoble, Franc