Involvement of peptidylarginine deiminase 4 in eosinophil extracellular trap formation and contribution to citrullinated histone signal in thrombi

Background: Extracellular traps formed by neutrophils (NETs) and eosinophils (EETs) have been described in coronary thrombi, contributing to thrombus stability. A key mechanism during NET formation is histone modification by the enzyme PAD4. Citrullinated histones, the product of PAD4 activity, are often attributed to neutrophils. Eosinophils also express high levels of PAD4. Objectives: We aimed to explore the contribution of PAD4 to EET formation. Methods: We performed immunohistological analyses on thrombi, including a large, intact, and eosinophil-containing thrombus retrieved from the right coronary artery using an aspiration catheter and stroke thrombi from thrombectomy retrieval. We studied eosinophils for their capability to form PAD4-dependent EETs in response to strong ET-inducing agonists as well as activated platelets and bacteria. Results: Histopathology and immunofluorescence microscopy identified a coronary thrombus rich in platelets and neutrophils, with distinct areas containing von Willebrand factor and citrullinated histone H3 (H3Cit). Eosinophils were also identified in leukocyte-rich areas. The majority of the H3Cit+ signal colocalized with myeloperoxidase, but some colocalized with eosinophil peroxidase, indicating EETs. Eosinophils isolated from healthy volunteers produced H3Cit+ EETs, indicating an involvement of PAD4 activity. The selective PAD4 inhibitor GSK484 blocked this process, supporting PAD4 dependence of H3Cit+ EET release. Citrullinated histones were also present in EETs produced in response to live Staphylococci. However, limited evidence for EETs was found in mouse models of venous thrombosis or infective endocarditis. Conclusion: As in NETosis, PAD4 can catalyze the formation of EETs. Inhibition of PAD4 decreases EET formation, supporting the future utility of PAD4 inhibitors as possible antithrombotic agents

Sterische und elektronische Einflüsse auf PNP Pincer Liganden in der Eisen(II) und Mangan(I) Chemie

Abweichender Titel nach Übersetzung der Verfasserin/des VerfassersBase metal catalysis is an emerging field in organometallic chemistry to replace precious metals by earth abundant metals. To achieve so, a suited ligand backbone to support the non-precious metals is needed, in order to get catalytic activity. The influence of well designed ligands on base metal chemistry is exampled on a series of iron(II) and manganese(II) compounds. The research bases on tridentate “pincer” ligands with a pyridine backbone connected with two phosphine donors (PNP-ligands). The ligands vary in the set-up of linkers (CH2, NH, NMe, O) and phosphine moiety PR2. A new class of iron(II) PNP pincer complexes, made up of two pincer ligands in different bonding modes (tridentate and bidentate) is described. The complexes of general formula κ3,κ2-[Fe(PNP)2X]+ are only observed when small phosphines (PR2; R = Me, Et, nPr, nBu, Ph) and a NH linker is apparent in the PNP ligands. In solution, the formation is inevitable, even when altering the stoichiometry. The 31P {1H} NMR gives rise to an A2B spin system for the coordinated phosphines, and a singlet for the vacant, non-coordinating phosphine. The X-ray structures reveal that a hydrogen bonding between NH linker and the pyridine nitrogen is stabilizing the coordination geometry. The distorted octahedral structure leads to a high degree of stress, which makes the bidentate ligand labile. Rearrangement to tridentate mode and displacement by carbon monoxide (CO) are possible. Carbonyl complexes of type [Fe(PNP)(CO)X2] are accessible, which are prone to CO release on thermal treatment, with increasing steric demand of the phosphine. Manganese(I) PNP pincer complexes of type [Mn(PNP)(CO)2H] were found to be pre-catalysts for the selective hydrogenation of aldehydes. Functional groups like ketones, nitriles, esters and olefins are tolerated. Among the selected PNP ligands, NH linkers delivered the best results. The results suggest that bifunctionality of the ligand along with ligand-metal cooperation is essential for the mechanism. Turnover numbers (TON) of up to 10.000 could be achieved. The hydrogenation proceeds at room temperature, without additives in protic media. Analogue rhenium(I) PNP pincer complexes [Re(PNP)(CO)2H] had inferior performance below 100 TON’s. Additionally, the hydrido complexes [Mn(PNP)(CO)2H] and [Re(PNP)(CO)2H] activate carbon dioxide (CO2) at ambient conditions. The 1,2-addition of CO2 leads to a series of formate complexes of the types [Mn(PNP)(CO)2(OCHO)] and [Re(PNP)(CO)2(OCHO)]. In summary, these results offer a guide for Mn(I) and Fe(II) pincer chemistry allowing to alter the chemical properties in a modular fashion.10

Finding Reliable Information on the Web Should and Can Still Be Improved

This paper addresses two major weaknesses of locating rather specific information on the Web: First, to find information for a specific topic is still quite difficult. Second, if located, the degree of reliability of the information is not clear. We explain that much progress has been made concerning the first issue, yet the real issue is never explicitly mentioned: The interaction between user and the search engine has to be good enough so that the search engine really knows what the user wants. We will discuss a new approach to solve this. Concerning the second aspect we will show that no serious large-scale attempts have been made to help users to judge the reliability of information found. We propose a set of measures that would change the situation dramatically

Crystal structure of the tetrahydrofuran disolvate of a 94:6 solid solution of [N2,N6-bis(di-tert-butylphosphanyl)pyridine-2,6-diamine]dibromidomanganese(II) and its monophosphine oxide analogue

The MnBr2 complex of N2,N6-bis(di-tert-butylphosphanyl)pyridine-2,6-diamine (1·MnBr2) co-crystallizes with 5.69% of the monophosphine oxide analogue (1O·MnBr2) and two tetrahydrofuran (THF) molecules, namely [N2,N6-bis(di-tert-butylphosphanyl)pyridine-2,6-diamine]dibromidomanganese(II)–[bis(di-tert-butylphosphanyl)({6-[(di-tert-butylphosphanyl)amino]pyridin-2-yl}amino)phosphine oxide]dibromidomanganese(II)–tetrahydrofuran (0.94/0.06/2), [MnBr2(C21H41N3P2)]0.94[MnBr2(C21H41N3OP2)]0.06·2C4H8O. The 1·MnBr2 and 1O·MnBr2 complexes are occupationally disordered about general positions. Both complexes feature square-pyramidal coordination of the MnII atoms. They are connected by weak N—H...Br hydrogen bonding into chains extending along [001]. The THF molecules are located between the layers formed by these chains. One THF molecule is involved in hydrogen bonding to an amine H atom

An iron(II) complex featuring κ3 and labile κ2-bound PNP pincer ligands - striking differences between CH2 and NH spacers

The final publication is available at https://doi.org/10.1039/C4DT01933D.Treatment of anhydrous FeCl2 with 2 equiv. of the pincer ligand PNP-Ph afforded the diamagnetic cationic octahedral complex [Fe(κ3-P,N,P-PNP)(κ2-P,N-PNP)Cl]+ featuring a κ2-P,N-bound PNP ligand. Preliminary reactivity studies revealed that the κ2-P,N-bound PNP ligand is labile reacting with CO to afford trans-[Fe(PNP-Ph)(CO)2Cl]+.Austrian Science Funds (FWF)Fundação para a Ciência e Tecnologia, Projecto Estratégic

Sustainable Synthesis of Quinolines and Pyrimidines Catalyzed by Manganese PNP Pincer Complexes

This study represents the first example an environmentally benign, sustainable, and practical synthesis of substituted quinolines and pyrimidines using combinations of 2-aminobenzyl alcohols and alcohols as well as benzamidine and two different alcohols, respectively. These reactions proceed with high atom efficiency via a sequence of dehydrogenation and condensation steps that give rise to selective C–C and C–N bond formations, thereby releasing 2 equiv of hydrogen and water. A hydride Mn­(I) PNP pincer complex recently developed in our laboratory catalyzes this process in a very efficient way. A total of 15 different quinolines and 14 different pyrimidines were synthesized in isolated yields of up to 91 and 90%, respectively

Chemoselective Hydrogenation of Aldehydes under Mild, Base-Free Conditions: Manganese Outperforms Rhenium

Several hydride Mn­(I) and Re­(I) PNP pincer complexes were applied as catalysts for the homogeneous chemoselective hydrogenation of aldehydes. Among these, [Mn­(PNP-<i>i</i>Pr)­(CO)₂(H)] was found to be one of the most efficient base metal catalysts for this process and represents a rare example which permits the selective hydrogenation of aldehydes in the presence of ketones and other reducible functionalities, such as CC double bonds, esters, or nitriles. The reaction proceeds at room temperature under base-free conditions with catalyst loadings between 0.1 and 0.05 mol% and a hydrogen pressure of 50 bar (reaching TONs of up to 2000). A mechanism which involves an outer-sphere hydride transfer and reversible PNP ligand deprotonation/protonation is proposed. Analogous isoelectronic and isostructural Re­(I) complexes were only poorly active

Chemoselective Hydrogenation of Aldehydes under Mild, Base-Free Conditions: Manganese Outperforms Rhenium

Several hydride Mn­(I) and Re­(I) PNP pincer complexes were applied as catalysts for the homogeneous chemoselective hydrogenation of aldehydes. Among these, [Mn­(PNP-<i>i</i>Pr)­(CO)₂(H)] was found to be one of the most efficient base metal catalysts for this process and represents a rare example which permits the selective hydrogenation of aldehydes in the presence of ketones and other reducible functionalities, such as CC double bonds, esters, or nitriles. The reaction proceeds at room temperature under base-free conditions with catalyst loadings between 0.1 and 0.05 mol% and a hydrogen pressure of 50 bar (reaching TONs of up to 2000). A mechanism which involves an outer-sphere hydride transfer and reversible PNP ligand deprotonation/protonation is proposed. Analogous isoelectronic and isostructural Re­(I) complexes were only poorly active