Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis

Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4–gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure

Supramolecular schiff base coordination chemistry : blueprints for self-assembling metallocavitands and nanotubes

Heptametallic zinc(II) and cadmium(II) clusters have been isolated after reacting the metal-acetate salts with large diameter [3+3] Schiff base macrocycles. Two tetrazinc complexes have been characterized and identified as intermediates in the formation of the heptazinc complexes. The heptametallic complexes are, in fact, templated by the Schiff base macrocycles, a process that has been investigated with ¹H NMR spectroscopy and single-crystal X-ray diffraction. In the solid-state the heptametallic complexes have a bowl-shaped geometry, reminiscent of organic cavitands, leading to them being called metallocavitands. Solid-state investigation of the heptazinc and heptacadmium metallocavitands showed they organize into capsules with a cavity volume of 150 and 215 ų, respectively. Solution dimerization was also observed in aromatic solvents and N,N-dimethylformamide (DMF). The thermodynamics of dimerization have been quantified by van’t Hoff analyses of association constants measured with variabletemperature, variable-concentration ¹H NMR spectroscopy. Both metallocavitands exhibit entropy-driven dimerization in all solvents in which dimerization occurs. Unusual for dimerization of cavitands, this entropy-driven process can be attributed to the expulsion of solvent from the monomeric cavity upon dimerization. Inside the cavity of heptacadmium metallocavitands is a μ₃-OH ligand where the proton is located at the base of the cavity and is capable of hydrogen bonding with guest molecules. The μ₃-OH proton resonance is observable in low temperature 1H NMR spectra and exhibits two-bond J-coupling with three cadmium ions. Within capsules of the heptacadmium metallocavitands there are eight Lewis-acidic sites accessible to guest molecules, six unsaturated cadmium(II) centers and two μ₃-OH ligands. Solid-state analysis shows that two DMF molecules are encapsulated in the heptacadmium capsule where they each simultaneously exhibit a host-guest hydrogen-bond and a dative metalligand interaction. New methodology has been developed that facilitates synthesis of polydentate [2+2] Schiff base macrocycles with unsymmetrical salphen pockets. Also a [3+3] macrocycle with triptycenyl substituents has been synthesized to prohibit alkali-metal induced solution aggregation. The one-pot twelve component head-to-tail self-assembly of Pt₄ rings directed by chelating imine-pyridyl donors has been demonstrated. These supramolecules exhibit extensive columnar organization in both solution and the solid-state, a phenomenon that imparts liquid crystalline properties on the macrocycles.Science, Faculty ofChemistry, Department ofGraduat

Synthesis of a Non-aggregating Bay-Unsubstituted Perylene Bisimide Dye with Latent Bromo Groups for C–C Cross Coupling

To address the absence of synthetic routes to access easily functionalizable, non-aggregating, and soluble bay-unsubstituted perylene bisimide dyes, an efficient, three-step, multigram-scale synthesis of the divergent building block <i>N</i>,<i>N</i>′-bis(4-bromo-2,6-diisopropylphenyl)perylene-3,4:9,10-tetracarboxylic bisimide is reported. Suzuki coupling yields new dyes that maintain excellent solubility and exhibit unity quantum yields in CHCl₃, THF, toluene, and CH₃CN. The methodology reported here enables access to dyes with sensitive functional groups such as aldehydes that are not accessible by traditional imidization routes

Economic consequences of increasing the conformity in accounting for uncertain tax benefits

Commentary during the development of FASB Interpretation no. 48 suggests the interpretation could be costly for firms because new disclosure requirements could be used by the IRS to more effectively challenge uncertain tax positions. Stock returns around FIN 48 pronouncements suggest investors were not concerned about an increase in tax costs, and investors responded favorably to initial disclosures required under FIN 48. However, we document a significant negative market reaction to subsequent news of a Senate inquiry into these disclosures consistent with investors revising their beliefs over the potential for additional tax costs.Event study Disclosures Taxes Tax contingency Uncertain tax benefits

Synthesis of a Non-aggregating Bay-Unsubstituted Perylene Bisimide Dye with Latent Bromo Groups for C–C Cross Coupling

To address the absence of synthetic routes to access easily functionalizable, non-aggregating, and soluble bay-unsubstituted perylene bisimide dyes, an efficient, three-step, multigram-scale synthesis of the divergent building block <i>N</i>,<i>N</i>′-bis(4-bromo-2,6-diisopropylphenyl)perylene-3,4:9,10-tetracarboxylic bisimide is reported. Suzuki coupling yields new dyes that maintain excellent solubility and exhibit unity quantum yields in CHCl₃, THF, toluene, and CH₃CN. The methodology reported here enables access to dyes with sensitive functional groups such as aldehydes that are not accessible by traditional imidization routes

Giant Electroactive M₄L₆ Tetrahedral Host Self-Assembled with Fe(II) Vertices and Perylene Bisimide Dye Edges

Self-assembly of octahedral Fe­(II) ions and linear perylene bisimide (PBI) dyes with 2,2′-bipyridine groups covalently attached at the imide positions quantitatively yields an Fe₄(PBI)₆ tetrahedron by the directional bonding approach. With an edge length of 3.9 nm and estimated internal volume >950 ų, tetrahedron <b>T</b> is one of the largest M₄L₆ tetrahedra ever reported. Importantly, many of the desirable photo- and electroactive properties of the PBI ligands are transferred to the nanoscale metallo­supra­molecule. Tetrahedron <b>T</b> absorbs strongly across the visible spectrum out to 650 nm and exhibits a total of 7 highly reversible electrochemical oxidation and reduction waves spanning a 3.0 V range. This facile cycling of 34 electrons between +18 and −16 charged species is likely enabled due to the porous nature of the tetrahedron that allows the necessary counterions to freely flow in and out of the host. Host–guest encapsulation of C₆₀ by <b>T</b> in acetonitrile was studied by ¹³C NMR spectroscopy, UV–vis spectroscopy, and ESI-MS, confirming that the tetrahedron is a suitable host for large, functional guest molecules