Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Hydroamination of alkynes catalyzed by a cationic rhodium(I) complex

The cationic Rh(I) dicarbonyl complex [{Rh((mim)₂CH₂)(CO)₂}⁺BPh₄⁻] (1), containing a bidentate bisimidazolylmethane ligand [mim = N-methylimidazol-2-yl], acts as an efficient catalyst for the intramolecular hydroamination of both terminal and nonterminal alkynes. The complex catalyzes the regioselective formation of nitrogen-containing heterocycles from aliphatic aminoalkynes and the cyclization of o-alkynylanilines to 2-substituted indoles in high yield.4 page(s

Intramolecular hydroamination catalyzed by cationic rhodium and iridium complexes with bidentate nitrogen-donor ligands

Cationic rhodium(I) and iridium(I) complexes of the general formula [M(N−N)(CO)₂]⁺[X]-, incorporating the bidentate heterocyclic nitrogen donor ligands (N−N) bis(1-methylimidazol-2-yl)methane (bim) and bis(1-pyrazolyl)methane (bpm), are efficient catalysts for hydroamination. The cyclization of an aliphatic aminoalkyne to the corresponding five-membered imine heterocycle was achieved in good yield with excellent regioselectivity using both rhodium and iridium catalysts. The nature of the counterion to the cationic catalysts has a significant effect on the rate of the hydroamination reaction and interionic contacts between the metal complexes and their counterions in solution were clearly visible by NMR spectroscopy using the nuclear Overhauser effect, indicating a strong anion/cation interaction in solution. The nature of the coligands also had a significant effect on the efficiency of the metal complexes as catalysts, and complexes containing phosphine coligands were less effective catalysts compared to those complexes containing CO coligands. The X-ray crystal structure of the new iridium(I) complex [Ir(bim)(CO)₂]⁺[BPh₄]⁻(2) is reported, as well as the synthesis and characterization of the Rh complex [Rh(bpm)(CO)₂]⁺[BPh₄]⁻(3).8 page(s

Late transition metal catalyzed intramolecular hydroamination : the effect of ligand and substrate structure

A series of cationic rhodium(I) and iridium(I) complexes of the type [M(N−N)(CO)₂][BPh₄] containing the imidazole-based bidentate nitrogen donor ligands (N−N), including bis(N-methylimidazol-2-yl)methane (bim) (1, a M = Rh, b M = Ir), bis(N-methylimidazol-2-yl)ketone (bik) (5, a M = Rh, b M = Ir), 1,1-bis(N-methylimidazol-2-yl)ethane (bie) (3, M = Rh), 2,2-bis(N-methylimidazol-2-yl)propane (bip) (4, M = Rh), and bis(N-methylbenzimidazol-2-yl)methane (bbnzim) (6a M = Rh, 6b M = Ir), were synthesized and characterized. Complexes incorporating the pyrazole analogue bis(1-pyrazolyl)methane (bpm) [M(bpm)(CO)₂][BPh₄] (2, a M = Rh, b M = Ir) were also prepared. The efficiency of each of the complexes as catalysts for the cyclization of 4-pentyn-1-amine to 2-methyl-1-pyrroline is reported. The influence of structural variations of the nitrogen donor ligand on the catalytic efficiency of cationic complexes of the type [M(N−N)(CO)₂][BPh4] for the hydroamination reaction was found to be much less than the influence of the nature of the counterion. The scope of the substrates for the intramolecular hydroamination of alkynamines was also investigated using Rh and Ir catalysts with the bim and bpm ligands, using 3-butyn-1-amine (7a), 3-pentyn-1-amine (7b), 4-phenyl-3-butyn-1-amine (7c), 4-pentyn-1-amine (8a), 4-hexyn-1-amine (8b), 5-phenyl-4-pentyn-1-amine (8c), 5-hexyn-1-amine (9), and 6-heptyn-1-amine (10) as substrates. The rhodium and iridium catalysts under investigation preferentially catalyze the formation of five-membered rings and do not catalyze the formation of four- or seven-membered rings. The effect of the substituents on the alkyne on the efficiency of hydroamination differentiates Rh(I) and Ir(I) and suggests the nature of the reactive metal-bound alkynyl intermediate.9 page(s

Mononuclear rhodium(I) complexes with chelating N-heterocyclic carbene ligands - Catalytic activity for intramolecular hydroamination

The mononuclear cationic RhI complexes [Rh(cod)(mdd)]+X⁻ and [Rh(CO)₂(mdd)]⁺X⁻ (X = BPh₄, PF₆) containing the chelating bidentate N-heterocyclic carbene ligand 1,1′-methylene-3,3′-dimethyldiimidazoline-2,2′-diylidene (mdd) have been synthesised and spectroscopically characterised. The complexes [Rh(cod)(mdd)]⁺BPh₄− and [Rh(CO)₂(mdd)]⁺PF₆⁻ have also been characterised by X-ray crystallography. The dicarbonyl complexes catalyse the intramolecular hydroamination of 4-pentyn-1-amine to 2-methyl-1-pyrroline.6 page(s

Cyclization of acetylenic amides using a cationic rhodium(I) complex

The cationic Rh(I) dicarbonyl complex [{Rh(bim)(CO)₂}⁺BPh₄⁻] 1, containing a bidentate bisimidazolylmethane ligand [bim refers to bis(N-methylimidazol-2-yl)methane] acts as a catalyst for the cyclization of alkynyl amides to produce lactams and N-acyl heterocyclic compounds.4 page(s

Rhodium(I) and iridium(I) complexes with bidentate N, N and P, N ligands as catalysts for the hydrothiolation of alkynes

Cationic iridium(I), rhodium(I) complexes containing bis(1-methylimidazol-2-yl)methane, bim, [M(bim)(CO)₂]BPh₄ (M = Ir(1), Rh(2)); bis(pyrazol-1-yl)methane, bpm, [M(bpm)(CO)₂]BPh₄ (M = Ir (3), Rh(4)) have been shown to be effective in catalysing the regioselective addition of thiophenol to a series of alkynes. Analogous cationic and neutral Ir(I), Rh(I) complexes with the novel mixed P,N-donor bidentate ligand 1-(2-diphenylphosphino)ethylpyrazole, PyP(5), [M(PyP)(COD)]BPh₄ (M = Ir(6), Rh(7), COD = 1,5-cyclooctadiene); [Rh(PyP)(COD)]BF4 (8); [Ir(PyP)(CO)₂]BPh₄(9); [Rh(PyP)(CO)₂]BF₄ (10); [M(PyP)(CO)Cl] (M = Ir(11), Rh(12)) have also been synthesised, and characterised by NMR. The solid-state structures of (6), (7), (11) and (12) have been determined by single-crystal X-ray diffraction analysis. The metal complexes (9)–(12) with the mixed P,N-donor ligand, PyP are in most cases more effective in promoting the hydrothiolation of alkynes in comparison with the analogous complexes (1)–(4) with N,N-donor ligands. The iridium complexes were significantly more effective than their rhodium analogues in promoting the hydrothioloation of alkynes. The cationic complexes (9) and (10) are more effective as catalysts for the hydrothiolation of alkynes than their neutral analogues (11) and (12).11 page(s