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We present a comprehensive study of the inhomogeneous mixed-valence compound, EuPd3S4, by electrical transport, X-ray diffraction, time-domain 151Eu synchrotron Mössbauer spectroscopy, and X-ray absorption spectroscopy measurements under high pressure. Electrical transport measurements show that the antiferromagnetic ordering temperature, TN, increases rapidly from 2.8 K at ambient pressure to 23.5 K at ~19 GPa and plateaus between ~19 and ~29 GPa after which no anomaly associated with TN is detected. A pressure-induced first-order structural transition from cubic to tetragonal is observed, with a rather broad coexistence region (~20 GPa to ~30 GPa) that corresponds to the TN plateau. Mössbauer spectroscopy measurements show a clear valence transition from approximately 50:50 Eu2+:Eu3+ to fully Eu3+ at ~28 GPa, consistent with the vanishing of the magnetic order at the same pressure. X-ray absorption data show a transition to a fully trivalent state at a similar pressure. Our results show that pressure first greatly enhances TN, most likely via enhanced hybridization between the Eu 4f states and the conduction band, and then, second, causes a structural phase transition that coincides with the conversion of the europium to a fully trivalent state.
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The delafossites are a class of layered metal oxides that are notable for being able to exhibit optical transparency alongside an in-plane electrical conductivity, making them promising platforms for the development of transparent conductive oxides. Pressure-induced polymorphism offers a direct method for altering the electrical and optical properties in this class, and although the copper delafossites have been studied extensively under pressure, the silver delafossites remain only partially studied. We report two new high-pressure polymorphs of silver ferrite delafossite, AgFeO2, that are stabilized above â¼6 and â¼14 GPa. In situ X-ray diffraction and vibrational spectroscopy measurements are used to examine the structural changes across the two phase transitions. The high-pressure structure between 6 and 14 GPa is assigned as a monoclinic C2/c structure that is analogous to the high-pressure phase reported for AgGaO2. Nuclear resonant forward scattering reveals no change in the spin state or valence state at the Fe3+ site up to 15.3(5) GPa.
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In Fig. 1b of this Article, 'Csf1r' was misspelt 'Csfr1'. In addition, in Extended Data Fig. 11b, owing to an error during figure formatting, the genes listed in the first column shifted down three rows below the first gene on the list, causing a mismatch between the gene names and their characteristics. These errors have been corrected online, and the original Extended Data Fig. 11b is provided as Supplementary Information to the accompanying Amendment.
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Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.
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Vasos Sanguíneos/citologia , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Células Endoteliais/classificação , Animais , Artérias/citologia , Arteríolas/citologia , Capilares/citologia , Feminino , Fibroblastos/classificação , Masculino , Camundongos , Miócitos de Músculo Liso/classificação , Especificidade de Órgãos , Pericitos/classificação , Análise de Célula Única , Transcriptoma , Veias/citologiaRESUMO
RATIONALE: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive. OBJECTIVE: To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype. METHODS AND RESULTS: We reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult Pdgfbret/ret mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult Pdgfbret/ret brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB. CONCLUSIONS: By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.
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Barreira Hematoencefálica/metabolismo , Pericitos/citologia , Animais , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/patologia , Proliferação de Células , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Linfocinas/deficiência , Linfocinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Pericitos/metabolismo , Pericitos/patologia , Fator de Crescimento Derivado de Plaquetas/deficiência , Fator de Crescimento Derivado de Plaquetas/genética , Análise de Célula Única , TranscriptomaRESUMO
Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.
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Capilares/anormalidades , Movimento Celular , Células Endoteliais/metabolismo , Veia Retiniana/anormalidades , Malformações Vasculares/embriologia , Proteína cdc42 de Ligação ao GTP/deficiência , Animais , Capilares/embriologia , Polaridade Celular/genética , Células Endoteliais/patologia , Camundongos , Camundongos Knockout , Pseudópodes/genética , Pseudópodes/metabolismo , Veia Retiniana/embriologia , Malformações Vasculares/genética , Malformações Vasculares/patologiaRESUMO
RATIONALE: Aberrant formation of blood vessels precedes a broad spectrum of vascular complications; however, the cellular and molecular events governing vascular malformations are not yet fully understood. OBJECTIVE: Here, we investigated the role of CDC42 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations. METHODS AND RESULTS: To avoid secondary systemic effects often associated with embryonic gene deletion, we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCMs). At the cellular level, loss of CDC42 function in brain endothelial cells (ECs) impairs their sprouting, branching morphogenesis, axial polarity, and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where EC proliferation is the most pronounced during brain development-the postnatal cerebellum-indicating that a high, naturally occurring EC proliferation provides a permissive state for the appearance of these malformations. Mechanistically, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)-MEK5 (mitogen-activated protein kinase kinase 5)-ERK5 (extracellular signal-regulated kinase 5) signaling and consequent detrimental overexpression of KLF (Kruppel-like factor) 2 and KLF4, recapitulating the hallmark mechanism for CCM pathogenesis. Through genetic approaches, we demonstrate that the coinactivation of Klf4 reduces the severity of vascular malformations in Cdc42 mutant mice. Moreover, we show that CDC42 interacts with CCMs and that CCM3 promotes CDC42 activity in ECs. CONCLUSIONS: We show that endothelial-specific deletion of Cdc42 elicits CCM-like cerebrovascular malformations and that CDC42 is engaged in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway.
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Vasos Sanguíneos/anormalidades , Proliferação de Células , Células Endoteliais/fisiologia , Deleção de Genes , Hemangioma Cavernoso do Sistema Nervoso Central/etiologia , Proteína cdc42 de Ligação ao GTP/genética , Animais , Animais Recém-Nascidos , Proteínas Reguladoras de Apoptose/genética , Encéfalo/irrigação sanguínea , Ciclo Celular/fisiologia , Proteína KRIT1/genética , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/metabolismo , MAP Quinase Quinase 5/metabolismo , MAP Quinase Quinase Quinase 3/metabolismo , Camundongos , Proteínas dos Microfilamentos/genética , Proteína cdc42 de Ligação ao GTP/metabolismoRESUMO
X-ray diffraction indicates that the structure of the recently discovered carbonaceous sulfur hydride (C-S-H) room-temperature superconductor is derived from previously established van der Waals compounds found in the H2S-H2 and CH4-H2 systems. Crystals of the superconducting phase were produced by a photochemical synthesis technique, leading to the superconducting critical temperature Tc of 288 K at 267 GPa. X-ray diffraction patterns measured from 124 to 178 GPa, within the pressure range of the superconducting phase, are consistent with an orthorhombic structure derived from the Al2Cu-type determined for (H2S)2H2 and (CH4)2H2 that differs from those predicted and observed for the S-H system at these pressures. The formation and stability of the C-S-H compound can be understood in terms of the close similarity in effective volumes of the H2S and CH4 components, and denser carbon-bearing S-H phases may form at higher pressures. The results are crucial for understanding the very high superconducting Tc found in the C-S-H system at megabar pressures.
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Pulmonary hypertension (PH) is a lethal condition, and current vasodilator therapy has limited effect. Antiproliferative strategies targeting platelet-derived growth factor (PDGF) receptors, such as imatinib, have generated promising results in animal studies. Imatinib is, however, a nonspecific tyrosine kinase inhibitor and has in clinical studies caused unacceptable adverse events. Further studies are needed on the role of PDGF signaling in PH. Here, mice expressing a variant of PDGF-B with no retention motif ( Pdgfbret/ret), resulting in defective binding to extracellular matrix, were studied. Following 4 wk of hypoxia, right ventricular systolic pressure, right ventricular hypertrophy, and vascular remodeling were examined. Pdgfbret/ret mice did not develop PH, as assessed by hemodynamic parameters. Hypoxia did, however, induce vascular remodeling in Pdgfbret/ret mice; but unlike the situation in controls where the remodeling led to an increased concentric muscularization of arteries, the vascular remodeling in Pdgfbret/ret mice was characterized by a diffuse muscularization, in which cells expressing smooth muscle cell markers were found in the interalveolar septa detached from the normally muscularized intra-acinar vessels. Additionally, fewer NG2-positive perivascular cells were found in Pdgfbret/ret lungs, and mRNA analyses showed significantly increased levels of Il6 following hypoxia, a known promigratory factor for pericytes. No differences in proliferation were detected at 4 wk. This study emphasizes the importance of extracellular matrix-growth factor interactions and adds to previous knowledge of PDGF-B in PH pathobiology. In summary, Pdgfbret/ret mice have unaltered hemodynamic parameters following chronic hypoxia, possibly secondary to a disorganized vascular muscularization.
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Modelos Animais de Doenças , Matriz Extracelular/patologia , Hipertensão Pulmonar/patologia , Hipóxia/fisiopatologia , Linfocinas/fisiologia , Músculo Liso Vascular/patologia , Fator de Crescimento Derivado de Plaquetas/fisiologia , Remodelação Vascular , Animais , Proliferação de Células , Células Cultivadas , Matriz Extracelular/metabolismo , Feminino , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Pericitos/metabolismo , Pericitos/patologia , Transdução de SinaisRESUMO
Using combined experimental and computational approaches, we show that at 43 GPa and 1300 K gallium phosphide adopts the super- Cmcm structure, here indicated with its Pearson notation oS24. First-principles enthalpy calculations demonstrate that this structure is more thermodynamically stable above â¼20 GPa than previously proposed polymorphs. In contrast to other polymorphs, the oS24 phase shows a strong bonding differentiation and distorted fivefold coordination geometries of both P atoms. The shortest bond of the phase is a single covalent P-P bond measuring 2.171(11) Å at synthesis pressure. Phosphorus dimerization in GaP sheds light on the nature of the super- Cmcm phase and provides critical new insights into the high-pressure polymorphism of octet semiconductors. Bond directionality and anisotropy explain the relatively low symmetry of this high-pressure phase.
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Recent major improvements in a number of imaging techniques now allow for the study of the brain in ways that could not be considered previously. Researchers today have well-developed tools to specifically examine the dynamic nature of the blood vessels in the brain during development and adulthood; as well as to observe the vascular responses in disease situations in vivo. This review offers a concise summary and brief historical reference of different imaging techniques and how these tools can be applied to study the brain vasculature and the blood-brain barrier integrity in both healthy and disease states. Moreover, it offers an overview on available transgenic animal models to study vascular biology and a description of useful online brain atlases.
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Barreira Hematoencefálica/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Neuroimagem/métodos , Animais , Humanos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios XRESUMO
PURPOSE OF REVIEW: Throughout history, development of novel microscopy techniques has been of fundamental importance to advance the vascular biology field.This review offers a concise summary of the most recently developed imaging techniques and discusses how they can be applied to vascular biology. In addition, we reflect upon the most important fluorescent reporters for vascular research that are currently available. RECENT FINDINGS: Recent advances in light sheet-based imaging techniques now offer the ability to live image the vascular system in whole organs or even in whole animals during development and in pathological conditions with a satisfactory spatial and temporal resolution. Conversely, super resolution microscopy now allows studying cellular processes at a near-molecular resolution. SUMMARY: Major recent improvements in a number of imaging techniques now allow study of vascular biology in ways that could not be considered previously. Researchers now have well-developed tools to specifically examine the dynamic nature of vascular development during angiogenic sprouting, remodeling and regression as well as the vascular responses in disease situations in vivo. In addition, open questions in endothelial and lymphatic cell biology that require subcellular resolution such as actin dynamics, junctional complex formation and stability, vascular permeability and receptor trafficking can now be approached with high resolution.
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Vasos Sanguíneos/metabolismo , Processamento de Imagem Assistida por Computador/métodos , HumanosRESUMO
Spinel-type crystals may possess complex and versatile chemical composition and crystal structure, which leads to difficulty in constructing relationships among the chemical composition, crystal structure, and intrinsic properties. In this work, we develop new empirical methods based on bond valences to estimate the intrinsic properties, namely, compressibility and thermal expansion of complex spinel-type crystals. The composition-weighted average of bond force constants in tetrahedral and octahedral coordination polyhedra is derived as a function of the composition-weighted average of bond valences, which can be calculated according to the experimental chemical composition and crystal structural parameters. We discuss the coupled effects of tetrahedral and octahedral frameworks on the aforementioned intrinsic properties. The bulk modulus could be quantitatively calculated from the composition-weighted average of bond force constants in tetrahedral and octahedral coordination polyhedra. In contrast, a quantitative estimation of the thermal expansion coefficient could be obtained from the composition-weighted average of bond force constants in octahedral coordination polyhedra. These empirical methods have been validated by the results obtained for a new complex quaternary spinel-type oxynitride Mg0.268Al2.577O3.733N0.267 as well as MgAl2O4 and Al2.85O3.45N0.55 from the literature. Further, these empirical methods have the potential to be extensively applied in other types of complex crystals.
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Phases of the iron-oxygen binary system are significant to most scientific disciplines, directly affecting planetary evolution, life, and technology. Iron oxides have unique electronic properties and strongly interact with the environment, particularly through redox reactions. The iron-oxygen phase diagram therefore has been among the most thoroughly investigated, yet it still holds striking findings. Here, we report the discovery of an iron oxide with formula Fe(4)O(5), synthesized at high pressure and temperature. The previously undescribed phase, stable from 5 to at least 30 GPa, is recoverable to ambient conditions. First-principles calculations confirm that the iron oxide here described is energetically more stable than FeO + Fe(3)O(4) at pressure greater than 10 GPa. The calculated lattice constants, equation of states, and atomic coordinates are in excellent agreement with experimental data, confirming the synthesis of Fe(4)O(5). Given the conditions of stability and its composition, Fe(4)O(5) is a plausible accessory mineral of the Earth's upper mantle. The phase has strong ferrimagnetic character comparable to magnetite. The ability to synthesize the material at accessible conditions and recover it at ambient conditions, along with its physical properties, suggests a potential interest in Fe(4)O(5) for technological applications.
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Dirac materials offer exciting opportunities to explore low-energy carrier dynamics and novel physical phenomena, especially their interaction with magnetism. In this context, this work focuses on studies of pressure control on the magnetic state of EuMnBi2, a representative magnetic Dirac semimetal, through time-domain synchrotron Mössbauer spectroscopy in151Eu. Contrary to the previous report that the antiferromagnetic order is suppressed by pressure above 4 GPa, we have observed robust magnetic order up to 33.1 GPa. Synchrotron-based x-ray diffraction experiment on a pure EuMnBi2sample shows that the tetragonal crystal lattice remains stable up to at least 31.7 GPa.
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The transition toward a carbon-neutral society based on renewable energies goes hand in hand with the availability of energy-efficient technologies. Magnetocaloric cooling is a very promising refrigeration technology to fulfill this role regarding cryogenic gas liquefaction. However, the current reliance on highly resource critical, heavy rare-earth-based compounds as magnetocaloric material makes global usage unsustainable. Here, we aim to mitigate this limitation through the utilization of a multicaloric cooling concept, which uses the external stimuli of isotropic pressure and magnetic field to tailor and induce magnetostructural phase transitions associated with large caloric effects. In this study, La0.7Ce0.3Fe11.6Si1.4 is used as a nontoxic, low-cost, low-criticality multiferroic material to explore the potential, challenges, and peculiarities of multicaloric cryocooling, achieving maximum isothermal entropy changes up to -28 J (kg K)-1 in the temperature range from 190 K down to 30 K. Thus, the multicaloric cooling approach offers an additional degree of freedom to tailor the phase transition properties and may lead to energy-efficient and environmentally friendly gas liquefaction based on designed-for-purpose, noncritical multiferroic materials.
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Claudin-5 (CLDN5) is an endothelial tight junction protein essential for blood-brain barrier (BBB) formation. Abnormal CLDN5 expression is common in brain disease, and knockdown of Cldn5 at the BBB has been proposed to facilitate drug delivery to the brain. To study the consequences of CLDN5 loss in the mature brain, we induced mosaic endothelial-specific Cldn5 gene ablation in adult mice (Cldn5iECKO). These mice displayed increased BBB permeability to tracers up to 10 kDa in size from 6 days post induction (dpi) and ensuing lethality from 10 dpi. Single-cell RNA sequencing at 11 dpi revealed profound transcriptomic differences in brain endothelial cells regardless of their Cldn5 status in mosaic mice, suggesting major non-cell-autonomous responses. Reactive microglia and astrocytes suggested rapid cellular responses to BBB leakage. Our study demonstrates a critical role for CLDN5 in the adult BBB and provides molecular insight into the consequences and risks associated with CLDN5 inhibition.
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Barreira Hematoencefálica , Células Endoteliais , Animais , Camundongos , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Claudina-5/genética , Claudina-5/metabolismo , Células Endoteliais/metabolismoRESUMO
High valent iron terminal imido species (Fe[double bond, length as m-dash]NR) have been shown to be key reactive intermediates in C-H functionalization. However, the detailed structure-reactivity relationship in Fe[double bond, length as m-dash]NR species derived from studies of structurally well-characterized high-valent Fe[double bond, length as m-dash]NR complexes are still scarce, and the impact of imido N-substituents (electron-donating vs. electron-withdrawing) on their electronic structures and reactivities has not been thoroughly explored. In this study, we report spectroscopic and computational studies on a rare S = 1 iron(iv)-bisimido complex featuring trifluoromethyl groups on the imido N-substituents, [(IPr)Fe(NC(CF3)2Ph)2] (2), and two closely related S = 0 congeners bearing alkyl and aryl substituents, [(IPr)Fe(NC(CMe3)2Ph)2] (3) and [(IPr)Fe(NDipp)2] (1), respectively. Compared with 1 and 3, 2 exhibits a decreased Fe[double bond, length as m-dash]NR bond covalency due to the electron-withdrawing and the steric effect of the N-substituents, which further leads to a pseudo doubly degenerate ground electronic structure and spin polarization induced ß spin density on the imido nitrogens. This unique electronic structure, which differs from those of the well-studied Fe(iv)-oxido complexes and many previously reported Fe(iv)-imido complexes, provides both kinetic and thermodynamic advantages for facile C-H activation, compared to the S = 0 counterparts.
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In nature, nonheme iron enzymes use dioxygen to generate high-spin iron(IV)=O species for a variety of oxygenation reactions. Although synthetic chemists have long sought to mimic this reactivity, the enzyme-like activation of O2 to form high-spin iron(IV) = O species remains an unrealized goal. Here, we report a metal-organic framework featuring iron(II) sites with a local structure similar to that in α-ketoglutarate-dependent dioxygenases. The framework reacts with O2 at low temperatures to form high-spin iron(IV) = O species that are characterized using in situ diffuse reflectance infrared Fourier transform, in situ and variable-field Mössbauer, Fe Kß x-ray emission, and nuclear resonance vibrational spectroscopies. In the presence of O2, the framework is competent for catalytic oxygenation of cyclohexane and the stoichiometric conversion of ethane to ethanol.
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BACKGROUND & AIMS: Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor activated by ligands that regulates genes related to vascular tone, oxidative stress, and fibrogenesis, pathways implicated in the development of cirrhosis and portal hypertension. This study aims at evaluating the effects of PPARα activation with fenofibrate on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl(4)-cirrhotic rats. METHODS: Mean arterial pressure (MAP), portal pressure (PP), and portal blood flow (PBF) were measured in cirrhotic rats treated with oral fenofibrate (25mg/kg/day, n=10) or its vehicle (n=12) for 7 days. The liver was then perfused and dose-relaxation curves to acetylcholine (Ach) were performed. We also evaluated Sirius Red staining of liver sections, collagen-I mRNA expression, and smooth muscle actin (α-SMA) protein expression, cyclo-oxygenase-1 (COX-1) protein expression, and cGMP levels in liver homogenates, and TXB(2) production in perfusates. Nitric oxide (NO) bioavailability and eNOS activation were measured in hepatic endothelial cells (HEC) isolated from cirrhotic rat livers. RESULTS: CCl(4) cirrhotic rats treated with fenofibrate had a significantly lower PP (-29%) and higher MAP than those treated with vehicle. These effects were associated with a significant reduction in hepatic fibrosis and improved vasodilatory response to acetylcholine. Moreover, a reduction in COX-1 expression and TXB(2) production in rats receiving fenofibrate and a significant increase in NO bioavailability in HEC with fenofibrate were observed. CONCLUSIONS: PPARα activation markedly reduced PP and liver fibrosis and improved hepatic endothelial dysfunction in cirrhotic rats, suggesting it may represent a new therapeutic strategy for portal hypertension in cirrhosis.