Imaging intact human organs from the organ to the cellular scale in three dimensions is a goal of biomedical imaging. To meet this challenge, we developed hierarchical phase-contrast tomography ...(HiP-CT), an X-ray phase propagation technique using the European Synchrotron Radiation Facility (ESRF)'s Extremely Brilliant Source (EBS). The spatial coherence of the ESRF-EBS combined with our beamline equipment, sample preparation and scanning developments enabled us to perform non-destructive, three-dimensional (3D) scans with hierarchically increasing resolution at any location in whole human organs. We applied HiP-CT to image five intact human organ types: brain, lung, heart, kidney and spleen. HiP-CT provided a structural overview of each whole organ followed by multiple higher-resolution volumes of interest, capturing organotypic functional units and certain individual specialized cells within intact human organs. We demonstrate the potential applications of HiP-CT through quantification and morphometry of glomeruli in an intact human kidney and identification of regional changes in the tissue architecture in a lung from a deceased donor with coronavirus disease 2019 (COVID-19).
Several metalloenzymes, including FeFe-hydrogenase, employ cofactors wherein multiple metal atoms work together with surrounding ligands that mediate heterolytic and concerted proton-electron ...transfer (CPET) bond activation steps. Herein, we report a new dinucleating PNNP expanded pincer ligand, which can bind two low-valent iron atoms in close proximity to enable metal-metal cooperativity (MMC). In addition, reversible partial dearomatization of the ligand's naphthyridine core enables both heterolytic metal-ligand cooperativity (MLC) and chemical non-innocence through CPET steps. Thermochemical and computational studies show how a change in ligand binding mode can lower the bond dissociation free energy of ligand C(sp
)-H bonds by ∼25 kcal mol
. H-atom abstraction enabled trapping of an unstable intermediate, which undergoes facile loss of two carbonyl ligands to form an unusual paramagnetic (
= ) complex containing a mixed-valent iron(0)-iron(i) core bound within a partially dearomatized PNNP ligand. Finally, cyclic voltammetry experiments showed that these diiron complexes show catalytic activity for the electrochemical hydrogen evolution reaction. This work presents the first example of a ligand system that enables MMC, heterolytic MLC and chemical non-innocence, thereby providing important insights and opportunities for the development of bimetallic systems that exploit these features to enable new (catalytic) reactivity.
The synthesis, characterization and catalytic activity of a new class of diruthenium hydrido carbonyl complexes bound to the tBuPNNP expanded pincer ligand is described. Reacting tBuPNNP with two ...equiv of RuHCl(PPh3)3(CO) at 140 °C produces an insoluble air‐stable complex, which was structurally characterized as Ru2(tBuPNNP)H(μ‐H)Cl(μ‐Cl)(CO)2 (1) using solid‐state NMR, IR and X‐ray absorption spectroscopies and follow‐up reactivity. A reaction with KOtBu results in deprotonation of a methylene linker to produce Ru2(tBuPNNP*)H(μ‐H)(μ‐OtBu)(CO)2 (3) featuring a partially dearomatized naphthyridine core. This enables metal‐ligand cooperative activation of H2 analogous to the mononuclear analogue, Ru(tBuPNP*)H(CO). In contrast to the mononuclear system, the bimetallic analogue 3 catalyzes the E‐selective semi‐hydrogenation of alkynes at ambient temperature and atmospheric H2 pressure with good functional group tolerance. Monitoring the semi‐hydrogenation of diphenylacetylene by 1H NMR spectroscopy shows the intermediacy of Z‐stilbene, which is subsequently isomerized to the E‐isomer. Initial findings into the mode of action of this system are provided, including the spectroscopic characterization of a polyhydride intermediate and the isolation of a deactivated species with a partially hydrogenated naphthyridine backbone.
Two do the job: Diruthenium hydrido carbonyl complexes bound to a PNNP expanded pincer ligand are described. Deprotonation of the methylene linkers enables cooperative activation of H2 allowing for the E‐selective semi‐hydrogenation of internal alkynes under mild conditions. Initial insights into the mechanism and the isolation of a deactivated species with an unusual structure are provided.
Co(HBMIMPh2)2(BF4)2 (1) HBMIMPh2=bis(1‐methyl‐4,5‐diphenyl‐1H‐imidazol‐2‐yl)methane was investigated for its electrocatalytic hydrogen evolution performance in DMF using voltammetry and during ...controlled potential/current electrolysis (CPE/CCE) in a novel in‐line product detection setup. Performances were benchmarked against three reported molecular cobalt hydrogen evolution reaction (HER) electrocatalysts, Co(dmgBF2)2(solv)2 (2) (dmgBF2=difluoroboryldimethylglyoximato), Co(TPP) (3) (TPP=5,10,15,20‐tetraphenylporphyrinato), and Co(bapbpy)Cl(Cl) (4) bapbpy=6,6′‐bis‐(2‐aminopyridyl)‐2,2′‐bipyridine, showing distinct performances differences with 1 being the runner up in H2 evolution during CPE and the best catalyst in terms of overpotential and Faradaic efficiency during CCE. After bulk electrolysis, for all of the complexes, a deposit on the glassy carbon electrode was observed, and post‐electrolysis X‐ray photoelectron spectroscopy (XPS) analysis of the deposit formed from 1 demonstrated only a minor cobalt contribution (0.23 %), mainly consisting of Co2+. Rinse tests on the deposits derived from 1 and 2 showed that the initially observed distinct activity was (partly) preserved for the deposits. These observations indicate that the molecular design of the complexes dictates the features of the formed deposit and therewith the observed activity.
Put down a deposit: The electrocatalytic hydrogen evolution performance of molecular complex Co(HBMIMPh2)2(BF4)2 (1) is studied in DMF. Bulk electrolysis demonstrates a competitive performance of 1 towards reported electrocatalysts in terms of H2 production and overpotential. Post‐electrolysis analysis reveals that a formed electrode deposit with minor cobalt content also significantly contributes to the observed hydrogen evolution activity.
Bulky tri‐isopropyl silyl (TIPS) substituents and deuterium atoms in the ligand design have been shown to enhance the site‐selective oxidation of aliphatic C−H bonds and the epoxidation of C=C bonds ...in non‐heme iron oxidation catalysis. In this work, a series of non‐heme iron complexes were developed by combining TIPS groups and deuterium atoms in the ligand. These bulky deuterated complexes show a significant increase in catalytic performance compared to their counterparts containing only TIPS groups or deuterium atoms. A broad range of substrates was oxidized with excellent yields, particularly, using Fe(OTf)2((S,S)‐TIPSBPBP‐D4) (1‐TIPS‐D4) (0.1 mol % to 1 mol %) via a fast or slow oxidant addition protocol, resulting in an overall improvement in catalytic performance. Notably, in the oxidation of the complex substrate trans‐androsterone acetate, the use of a slow addition protocol and a lower catalyst loading of 1‐TIPS‐D4 resulted in significant increases in reaction efficiency. In addition, kinetic and catalytic studies showed that deuteration does not affect the catalytic activity and the secondary C−H site‐selectivity but increases the catalysts’ lifetime resulting in higher conversion/yield. Accordingly, the yield of selectively oxidized secondary C−H products also increases with the overall yield by using the bulky deuterated iron complexes as catalysts. These catalytic improvements of the bulky deuterated complexes exemplify the enhanced design of ligands for homogeneous oxidation catalysis.
A series of non‐heme iron complexes were developed by combining tri‐isopropyl silyl (TIPS) groups and deuterium atoms in the ligand. These bulky deuterated complexes show a significant increase in catalytic performance compared to their counterparts containing only TIPS groups or deuterium atoms. A broad range of substrates was oxidized with excellent yields, particularly, using Fe(OTf)2((S,S)‐TIPSBPBP‐D4) (1‐TIPS‐D4) (0.1 mol % to 1 mol %) via a fast or slow oxidant addition protocol, resulting in an overall improvement in catalytic performance.
Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for ...TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3−/− animals.
Smad3−/− animals developed aortic aneurysms rapidly, resulting in premature death. Aortic wall immunohistochemistry showed no increase in extracellular matrix and collagen accumulation, nor loss of vascular smooth muscle cells (VSMCs) but instead revealed medial elastin disruption and adventitial inflammation. Remarkably, matrix metalloproteases (MMPs) were not activated in VSMCs, but rather specifically in inflammatory areas. Although Smad3−/− aortas showed increased nuclear pSmad2 and pErk, indicating TGF-β receptor activation, downstream TGF-β-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3−/− aortas implied that aortic damage and TGF-β receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-β activated transcription resulted in increased Smad3−/− VSMC proliferation.
Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibilities for treatment of SMAD3 patients; instead of targeting TGF-β signaling, immune suppression may be more beneficial.
•Smad3 deficiency leads to aortic aneurysms and sudden death in Smad3 knockout mice.•Upstream TGF-β receptor signaling is activated, yet downstream TGF-β-activated transcription is impaired in Smad3-/- VSMCs•Improper TGF-β induced downstream gene activation in Smad3-/- VSMCs impairs ECM formation and weakens aortic structure
Mutations in the Smad3 gene cause aortic aneurysms and joint disorders. Since aneurysm growth is highly unpredictable in Smad3 patients, early diagnosis is of vital importance. Here we identify the molecular basis for this unpredictable and acute aneurysm growth using Smad3 knockout mice. Dysregulation of the downstream TGFβ signaling pathway due to absence of Smad3 weakens the extracellular matrix of vascular smooth muscle cells and changes the aortic composition, thereby leading to the attraction of immune cells. These findings provide a rationale for the variable clinical outcome in Smad3 patients and open up new intervention possibilities.
A series of mononuclear iron(II) and zinc(II) complexes of the new chiral Py(ProMe)2 ligand (Py(ProMe)2 = 2,6-bis(S)-2-(methyloxycarbonyl)-1-pyrrolidinylmethylpyridine) have been prepared. The ...molecular geometry in the solid state (X-ray crystal structures) of the complexes FeCl2(Py(ProMe)2) (1), ZnCl2(Py(ProMe)2) (2), Fe(OTf)2(Py(ProMe)2) (3), Fe(Py(ProMe)2)(OH2)2(OTf)2 (4), and Zn(OTf)(Py(ProMe)2)(OTf) (5) are reported. They all show a meridional NN'N coordination of the Py(ProMe)2 ligand. The bis-chloride derivatives 1 and 2 represent neutral isostructural five-coordinated complexes with a distorted geometry around the metal center. Unusual seven-coordinate iron(II) complexes 3 and 4 having a pentagonal bipyramidal geometry were obtained using weakly coordinating triflate anions. The reaction of Zn(OTf)2 with the Py(ProMe)2 ligand afforded complex 5 with a distorted octahedral geometry around the zinc center. All complexes were formed as single diastereoisomers. In the case of complexes 3-5, the oxygen atoms of both carbonyl groups of the ligand are also coordinated to the metal. The stereochemistry of the coordinated tertiary amine donors in complexes 3-5 is of opposite configuration as in complexes 1 and 2 as a result of the planar penta-coordination of the ligand Py(ProMe)2. Complexes 1, 2, and 5 have an overall -configuration at their metal center, while the Fe(II) ion in complexes 3 and 4 has the opposite delta-configuration (crystal structures and CD measurements). The magnetic moments of iron complexes 1, 3, and 4 correspond to that of high-spin d6 Fe(II) complexes. The solution structures of complexes 1-5 were characterized by means of UV-vis, IR, conductivity, and CD measurements and their electrochemical behavior. These studies showed that the coordination environment of 1 and 2 observed in the solid state is maintained in solution. In coordinating solvents, the triflate anion (3, 5) or water (4) co-ligands of complexes 3-5 are replaced by solvent molecules with retention of the original pentagonal bipyramidal and octahedral geometry, respectively.
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