A Homologous Series of Cobalt, Rhodium, and Iridium Metalloradicals

We herein present a series of d7 trimethylphosphine complexes of group 9 metals that are chelated by the tripodal tetradentate tris(phosphino)silyl ligand [SiP^(iPr)_3]H ([SiP^(iPr)_3] = (2_(-i)Pr_2PC_6H_4)_3Si^–). Both electron paramagnetic resonance (EPR) simulations and density functional theory (DFT) calculations indicate largely metalloradical character. These complexes provide a rare opportunity to compare the properties between the low-valent metalloradicals of the second- and third-row transition metals with the corresponding first-row analogues

E−H Bond Activation Reactions (E = H, C, Si, Ge) at Ruthenium: Terminal Phosphides, Silylenes, and Germylenes

The placement of a strongly trans-influencing ligand on a ruthenium center opposite an anchoring silyl group of the tetradentate tripodal tris(phosphino)silyl ligand, [SiP^(Ph)_3]^− ([SiP^(Ph)_3]^− = tris(2-(diphenylphosphino)phenyl)silyl), has been explored. Installation of alkyl or terminal phosphide ligands trans to the anchoring silyl group affords the complexes [SiPPh3]RuR (R = Me (2), CH_2Ph (4), PPh_2 (5), P^iPr_2 (6)). Complexes 2, 4, and 5 are thermally unstable. Complexes 2 and 4 decay to the cyclometalated complex [SiP^(Ph)_2P′^(Ph)]Ru (3), whereas complex 5 decays to the cyclometalated phosphine adduct [SiP^(Ph)_2P′^(Ph)]Ru(PHPh_2) (7). Complex 3 is found to effect E−H (E = H, C, Si, Ge) bond activation of substrates such as secondary silanes and germanes to yield the structurally unusual silylene complexes [SiP^(Ph)_3]Ru(H)(SiRR′) (R = R′ = Ph (10a), R = Ph R′ = Me (10b)) and the germylene complex [SiP^(Ph)_3]Ru(H)(GeR_2) (R = Ph) (11) via double E−H activation transformations. Both theory and experiments suggest electrophilic character at the silylene moiety. Reaction of 3 with catecholborane, in contrast to silanes and germanes, results in insertion of the B−H unit into the M−C bond of the cyclometalated species to yield the borate complex [SiP^(Ph)_2P^(Ph)-B(cat)]Ru(μ-H) (14). Complex 3 also reacts with bis(catecholato)diboron to yield a similar complex, [SiP^(Ph)_2P^(C6H3B(cat))-B(cat)]Ru(μ-H) (15), with selective borylation of an ortho C−H bond

Dinitrogen Complexes of Sulfur-Ligated Iron

We report a unique class of dinitrogen complexes of iron featuring sulfur donors in the ancillary ligand. The ligands utilized are related to the recently studied tris(phosphino)silyl ligands (2-R_2PC_6H_4)_3Si (R = Ph, iPr) but have one or two phosphine arms replaced with thioether donors. Depending on the number of phosphine arms replaced, both mononuclear and dinuclear iron complexes with dinitrogen are accessible. These complexes contribute to a desirable class of model complexes that possess both dinitrogen and sulfur ligands in the immediate iron coordination sphere

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Light-induced structural changes and the site of O=O bond formation in PSII caught by XFEL

Photosystem II (PSII) is a huge membrane-protein complex consisting of 20 different subunits with a total molecular mass of 350 kDa for a monomer. It catalyses light-driven water oxidation at its catalytic centre, the oxygen-evolving complex (OEC). The structure of PSII has been analysed at 1.9 Å resolution by synchrotron radiation X-rays, which revealed that the OEC is a Mn4CaO5 cluster organized in an asymmetric, 'distorted-chair' form. This structure was further analysed with femtosecond X-ray free electron lasers (XFEL), providing the 'radiation damage-free' structure. The mechanism of O=O bond formation, however, remains obscure owing to the lack of intermediate-state structures. Here we describe the structural changes in PSII induced by two-flash illumination at room temperature at a resolution of 2.35 Å using time-resolved serial femtosecond crystallography with an XFEL provided by the SPring-8 ångström compact free-electron laser. An isomorphous difference Fourier map between the two-flash and dark-adapted states revealed two areas of apparent changes: around the QB/non-haem iron and the Mn4CaO5 cluster. The changes around the QB/non-haem iron region reflected the electron and proton transfers induced by the two-flash illumination. In the region around the OEC, a water molecule located 3.5 Å from the Mn4CaO5 cluster disappeared from the map upon two-flash illumination. This reduced the distance between another water molecule and the oxygen atom O4, suggesting that proton transfer also occurred. Importantly, the two-flash-minus-dark isomorphous difference Fourier map showed an apparent positive peak around O5, a unique μ4-oxo-bridge located in the quasi-centre of Mn1 and Mn4 (refs 4,5). This suggests the insertion of a new oxygen atom (O6) close to O5, providing an O=O distance of 1.5 Å between these two oxygen atoms. This provides a mechanism for the O=O bond formation consistent with that proposed previousl

Investigations on Low-Valent Group 8 and 9 Metalloradicals

Tetradentate, monoanionic, tris(phosphino)silyl ligands were chelated to group 8 and 9 transition metals to stabilize complexes with unusual oxidation states and/or geometries. Initial studies with the [SiPPh3]− ligand on ruthenium established the flexibility of this ancillary ligand in stabilizing complexes with strongly trans influencing ligands in trans dispositions. A related ligand scaffold, [SiPiPr3]−, was subsequently used to stabilize mononuclear complexes of Ru(I) and Os(I), the first examples to be isolated and thoroughly chracterized. EPR spectroscopy and DFT calculations supported their metalloradical character, and further studies highlighted their reactivity in both one- and two-electron redox processes. The ability of the [SiPiPr3]− scaffold to stabilize d7 metalloradicals of group 8 metals was extended to group 9 metals, and a series of d7 complexes of cobalt, rhodium, and iridium were synthesized in which their ancillary ligands, oxidation states, spin states, and geometry are conserved. Similar to the previously reported [SiPiPr3]Fe(N2) complex, the related [SiPiPr3]Ru(N2) complex was shown to exhibit N−N coupling of organic azides to yield azoarenes catalytically. Detailed mechanistic studies conclusively showed that the Ru(III) imide species, whose iron analog is the key intermediate in the [SiPiPr3]Fe system, is not involved in the mechanism for the [SiPiPr3]Ru system. Instead, a mechanism in which free nitrene is released during the catalytic cyle is favored. Finally, hybrid ligands with multiple thioether donors in place of phosphine donors on the [SiPR3]− scaffold were synthesized to stabilize a number of dinitrogen complex of iron. These complexes featured rare examples of S−Fe−N2 linkages