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Dalton Transactions (Cambridge, England... Jun 2024Nuclear magnetic resonance (NMR) chemical shifts and the magnetically induced current density (MICD) susceptibility of four osmium containing molecules have been...
Nuclear magnetic resonance (NMR) chemical shifts and the magnetically induced current density (MICD) susceptibility of four osmium containing molecules have been calculated at the density functional theory (DFT) level using three relativistic levels of theory. The calculations were performed at the quasi-relativistic level using an effective core potential (ECP) for Os, at the all-electron scalar exact two-component (X2C) relativistic level, and at the relativistic X2C level including spin-orbit coupling (SO-X2C). In earlier studies, the osmapentalene (1) and the osmapentalynes (2 and 3) were considered Craig-type Möbius aromatic and it was suggested that the analogous osmium compound (4) is Craig-type Möbius antiaromatic. Here, the ring-current strengths were obtained with the gauge including magnetically induced currents (GIMIC) method by integrating the MICD susceptibility passing through planes that intersect chemical bonds and by line integration of the induced magnetic field using Ampère-Maxwell's law. The ring-current calculations suggest that 1, 2 and 3 are weakly aromatic and that 4 is nonaromatic. The accuracy of the MICD susceptibility was assessed by comparing calculated NMR chemical shifts to available experimental data. Visualization of the MICD susceptibility shows that the ring current does not pass from one side of the molecular plane to the other, which means that the MICD susceptibility of the studied molecules does not exhibit any Möbius topology as one would expect for Craig-type Möbius aromatic and for Craig-type Möbius antiaromatic molecules. Thus, molecules 1-3 are not Craig-type Möbius aromatic and molecule 4 is not Craig-type Möbius antiaromatic as previously suggested. Calculations of the H NMR and C NMR chemical shifts of atoms near the Os atom show the importance of including spin-orbit effects. Overall, our study revisits the understanding of the aromaticity of organometallic molecules containing transition metals.
PubMed: 38888198
DOI: 10.1039/d4dt01110d -
Frontiers in Endocrinology 2024Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear,...
Deficiency of glucocorticoid receptor in bone marrow adipocytes has mild effects on bone and hematopoiesis but does not influence expansion of marrow adiposity with caloric restriction.
INTRODUCTION
Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids.
METHODS
In this study, we utilized a recently described mouse model () to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. ) whilst maintaining GR expression in other adipose depots.
RESULTS
Mice lacking GR in BMAds ( ) and control mice ( ) were fed or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and μCT revealed no difference in BMAT accumulation between control or mice. Differences in BMAd size were not observed between and control mice. Interestingly, mice had decreased circulating white blood cell counts 4 h into the light cycle.
DISCUSSION
In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.
Topics: Animals; Receptors, Glucocorticoid; Caloric Restriction; Mice; Adipocytes; Adiposity; Female; Hematopoiesis; Bone Marrow; Mice, Knockout; Bone and Bones; Mice, Inbred C57BL; Adipose Tissue; Male; Metabolism, Inborn Errors
PubMed: 38887268
DOI: 10.3389/fendo.2024.1397081 -
Inorganic Chemistry Jun 2024The article highlights the cooperative impact of azoheteroarenes [abbt: 2,2'-azobis(benzothiazole), L1-L3; bmpd: ()-1,2-bis(1-methyl-1-pyrazole-3-yl) diazene, L4] and...
The article highlights the cooperative impact of azoheteroarenes [abbt: 2,2'-azobis(benzothiazole), L1-L3; bmpd: ()-1,2-bis(1-methyl-1-pyrazole-3-yl) diazene, L4] and coligands [bpy: 2,2'-bipyridine; pap: 2-phenylazopyridine] in tuning radical (N-N) versus nonradical (N═N) states of L on selective Os-platforms in structurally/spectroscopically characterized monomeric []ClO-[]ClO and [](ClO)-[](ClO)/[](ClO)-[](ClO), respectively. The preferred -configuration of L in the complexes prevented obtaining ligand bridged dimeric species. It revealed that {Os(bpy)} facilitated the stabilization of both nonradical ([](ClO)-[](ClO)) and radical ([]ClO-[]ClO) states of L1/L2, while it delivered exclusively the radical form for L3 in []ClO. In contrast, {Os(pap)} generated radical states of L1-L3 in []ClO-[]ClO, respectively, without any alteration of the redox state of Os and azo (N═N) function of the pap coligand. The neutral state of L4 was, however, ascertained in [](ClO) or [](ClO) irrespective of the nature of the metal fragment {Os(bpy)} or {Os(pap)}, respectively. Switching between radical and nonradical forms of L in the complexes as a function L and coligand could be addressed based on their relative FMO (frontier molecular orbital) energies. Multiple close redox steps of the complexes extended a competitive electron transfer scenario between the redox active components including metal/L/bpy/pap, leading to delicate electronic forms in each case.
PubMed: 38870544
DOI: 10.1021/acs.inorgchem.4c01384 -
Bioinorganic Chemistry and Applications 2024X-ray crystallography, spectroscopy, computational methods, molecular docking studies, and DNA-binding studies have been useful in the investigations of intermolecular...
Molecular Structure, Spectroscopic, Frontier Molecular Orbital Analysis, Molecular Docking Studies, and DNA-Binding Studies of Osmium(II)-Cymene Complexes with Aryl Phosphine and Aryl Phosphonium Assemblies.
X-ray crystallography, spectroscopy, computational methods, molecular docking studies, and DNA-binding studies have been useful in the investigations of intermolecular and intramolecular interactions of osmium-cymene oxalato complexes with aryl phosphine and aryl phosphonium groups in both primary and secondary coordination spheres, respectively. Molecular structures of the novel complexes PPh[Os(--cymene)Br(--CO)] () and [Os(--cymene) (--CO)PPh] () were resolved by single-crystal X-ray diffraction (XRD). Primary and secondary coordination sphere contacts were investigated using Hirshfeld surface analysis which was supported by molecular docking (MD) studies. The MD data obtained predicted significant differences in binding energy across three receptors for the two osmium complexes. An DNA-binding study was accomplished using UV-Vis spectroscopy which showed that both and bond with DNA through an intercalation approach. The optimized molecular geometry, frontier molecular orbital (E and E) energies, global electrophilicity index (), chemical hardness (), chemical potential (), and the energy band gap (E-E) were calculated utilizing density functional theory (DFT) methods. Computed structural parameters (bond lengths and angles) support the experimental single-crystal XRD data.
PubMed: 38840845
DOI: 10.1155/2024/6697523 -
Journal of Lipid Research May 2024Contrast-enhanced computed tomography (CECT) offers a non-destructive approach to studying adipose tissue in 3D. Several contrast-enhancing staining agents (CESAs) have...
Contrast-enhanced computed tomography (CECT) offers a non-destructive approach to studying adipose tissue in 3D. Several contrast-enhancing staining agents (CESAs) have been explored, whereof osmium tetroxide (OsO) is the most popular nowadays. However, due to the toxicity and volatility of the conventional OsO, alternative CESAs with similar staining properties were desired. Hf-WD 1:2 POM and Hexabrix have proven effective for structural analysis of adipocytes using CECT, but fail to provide chemical information. This study introduces isotonic Lugol's iodine (IL) as an alternative CESA for adipose tissue analysis, comparing its staining potential with Hf-WD 1:2 POM and Hexabrix in murine caudal vertebrae (MCV) and bovine muscle tissue (BMT) strips. Single and sequential staining protocols were compared to assess the maximization of information extraction from each sample. The study investigated interactions, distribution, and reactivity of iodine species towards biomolecules using simplified model systems and assesses the potential of the CESA to provide chemical information. (Bio)chemical analyses on whole tissues revealed that differences in adipocyte grey values post-IL staining were associated with chemical distinctions between BMT and MCV. More specific, a difference in degree of unsaturation of fatty acids was identified as a likely contributor, though not the sole determinant of grey value differences. This research sheds light on the potential of IL as a CESA, offering both structural and chemical insights into adipose tissue composition.
PubMed: 38823780
DOI: 10.1016/j.jlr.2024.100572 -
Frontiers in Neurology 2024Despite its location near infection-prone areas, the human inner ear demonstrates remarkable resilience. This suggests that there are inherent instruments deterring the...
BACKGROUND
Despite its location near infection-prone areas, the human inner ear demonstrates remarkable resilience. This suggests that there are inherent instruments deterring the invasion and spread of pathogens into the inner ear. Here, we combined high-resolution light microscopy, super-resolution immunohistochemistry (SR-SIM) and synchrotron phase contrast imaging (SR-PCI) to identify the protection and barrier systems in the various parts of the human inner ear, focusing on the lateral wall, spiral ganglion, and endolymphatic sac.
MATERIALS AND METHODS
Light microscopy was conducted on mid-modiolar, semi-thin sections, after direct glutaraldehyde/osmium tetroxide fixation. The tonotopic locations were estimated using SR-PCI and 3D reconstruction in cadaveric specimens. The sections were analyzed for leucocyte and macrophage activity, and the results were correlated with immunohistochemistry using confocal microscopy and SR-SIM.
RESULTS
Light microscopy revealed unprecedented preservation of cell anatomy and several macrophage-like cells that were localized in the cochlea. Immunohistochemistry demonstrated IBA1 cells frequently co-expressing MHC II in the spiral ganglion, nerve fibers, lateral wall, spiral limbus, and tympanic covering layer at all cochlear turns as well as in the endolymphatic sac. RNAscope assays revealed extensive expression of fractalkine gene transcripts in type I spiral ganglion cells. CD4 and CD8 cells occasionally surrounded blood vessels in the modiolus and lateral wall. TMEM119 and P2Y12 were not expressed, indicating that the cells labeled with IBA1 were not microglia. The round window niche, compact basilar membrane, and secondary spiral lamina may form protective shields in the cochlear base.
DISCUSSION
The results suggest that the human cochlea is surveilled by dwelling and circulating immune cells. Resident and blood-borne macrophages may initiate protective immune responses via chemokine signaling in the lateral wall, spiral lamina, and spiral ganglion at different frequency locations. Synchrotron imaging revealed intriguing protective barriers in the base of the cochlea. The role of the endolymphatic sac in human inner ear innate and adaptive immunity is discussed.
PubMed: 38817543
DOI: 10.3389/fneur.2024.1355785 -
In-cell Catalysis by Tethered Organo-Osmium Complexes Generates Selectivity for Breast Cancer Cells.Chembiochem : a European Journal of... May 2024Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi-targeting strategy to overcome drug resistance. Nonetheless, many in-cell catalysts in...
Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi-targeting strategy to overcome drug resistance. Nonetheless, many in-cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os-based 16-electron half-sandwich ('piano stool') catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple-negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin-bound in the extracellular medium, while cellular accumulation studies identified an energy-dependent, protein-mediated Os accumulation pathway, consistent with albumin-mediated uptake. Importantly, the tethered Os complex was active for in-cell transfer hydrogenation catalysis, initiated by co-administration of a non-toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non-tumorigenic cells.
PubMed: 38785030
DOI: 10.1002/cbic.202400374 -
Journal of Synchrotron Radiation Jul 2024Despite the increased brilliance of the new generation synchrotron sources, there is still a challenge with high-resolution scanning of very thick and absorbing samples,...
Despite the increased brilliance of the new generation synchrotron sources, there is still a challenge with high-resolution scanning of very thick and absorbing samples, such as a whole mouse brain stained with heavy elements, and, extending further, brains of primates. Samples are typically cut into smaller parts, to ensure a sufficient X-ray transmission, and scanned separately. Compared with the standard tomography setup where the sample would be cut into many pillars, the laminographic geometry operates with slab-shaped sections significantly reducing the number of sample parts to be prepared, the cutting damage and data stitching problems. In this work, a laminography pipeline for imaging large samples (>1 cm) at micrometre resolution is presented. The implementation includes a low-cost instrument setup installed at the 2-BM micro-CT beamline of the Advanced Photon Source. Additionally, sample mounting, scanning techniques, data stitching procedures, a fast reconstruction algorithm with low computational complexity, and accelerated reconstruction on multi-GPU systems for processing large-scale datasets are presented. The applicability of the whole laminography pipeline was demonstrated by imaging four sequential slabs throughout an entire mouse brain sample stained with osmium, in total generating approximately 12 TB of raw data for reconstruction.
PubMed: 38771775
DOI: 10.1107/S1600577524002923 -
The Journal of Physical Chemistry. A May 2024The catalyzed electrochemical oxidation of ammonia to nitrogen (AOR) is an important fuel-cell half-reaction that underpins a future nitrogen-based energy economy. Our...
The catalyzed electrochemical oxidation of ammonia to nitrogen (AOR) is an important fuel-cell half-reaction that underpins a future nitrogen-based energy economy. Our laboratory has reported spontaneous chemical and electrochemical oxidation of ammonia to dinitrogen via reaction of ammonia with the metal-metal bonded diruthenium complex Ru(chp)OTf (chp = 2-chloro-6-hydroxypyridinate, TfO = trifluoromethanesulfonate). This complex facilitates electrocatalytic ammonia oxidation at mild applied potentials of -255 mV vs ferrocene, which is the [Ru(chp)(NH)] redox potential. We now report a comprehensive computational investigation of possible mechanisms for this reaction and electronic structure analysis of key intermediates therein. We extend this analysis to proposed second-generation electrocatalysts bearing structurally similar fhp and hmp (2-fluoro-6-hydroxypyridinate and 2-hydroxy-6-methylpyridinate, respectively) equatorial ligands, and we further expand this study from Ru to analogous Os cores. Predicted M redox potentials, which we expect to correlate with experimental AOR overpotential, depend strongly on the identity of the metal center, and to a lesser degree on the nature of the equatorial supporting ligand. Os complexes are easier to oxidize than analogous Ru complexes by ∼640 mV, on average. In contrast to mono-Ru catalysts, which oxidize ammonia via a rate-limiting activation of the strong N-H bond, we find lowest-energy reaction pathways for Ru and Os complexes that involve direct N-N bond formation onto electrophilic intermediates having terminal amido, imido, or nitrido groups. While transition state energies for Os complexes are high, those for Ru complexes are moderate and notably lower than those for mono-Ru complexes. We attribute these lower barriers to enhanced electrophilicity of the Ru intermediates, which is a consequence of their metal-metal bonded structure. Os intermediates are found to be, surprisingly, less electrophilic, and we suggest that Os complexes may require access to oxidation states higher than Os in order to perform AOR at reasonable reaction rates.
PubMed: 38742806
DOI: 10.1021/acs.jpca.4c02490 -
Molecules (Basel, Switzerland) May 2024-Tetrahexylporphyrin was converted to its corresponding 7,8-dihydroxychlorin using an osmium tetroxide-mediated dihydroxylation strategy. Its diol moiety was shown to be...
-Tetrahexylporphyrin was converted to its corresponding 7,8-dihydroxychlorin using an osmium tetroxide-mediated dihydroxylation strategy. Its diol moiety was shown to be able to undergo a number of subsequent oxidation reactions to form a chlorin dione and porpholactone, the first -alkylporphyrin-based porphyrinoid containing a non-pyrrolic building block. Further, the diol chlorin was shown to be susceptible to dehydration, forming the porphyrin enol that is in equilibrium with its keto-chlorin form. The -hexylchlorin dione could be reduced and it underwent mono- and bis-methylation reactions using methyl-Grignard reagents, and trifluoromethylation using the Ruppert-Prakash reagent. The optical and spectroscopic properties of the products are discussed and contrasted to their corresponding -aryl derivatives (where known). This contribution establishes -tetrahexyl-7,8-dihydroxychlorins as a new and versatile class of chlorins that is susceptible to a broad range of conversions to generate functionalized chlorins and a pyrrole-modified chlorin analogue.
PubMed: 38731635
DOI: 10.3390/molecules29092144