Clinical and pathological characterization of FLNC-related myofibrillar myopathy caused by founder variant c.8129G>A in Hong Kong Chinese.

FLNC-related myofibrillar myopathy could manifest as autosomal dominant late-onset slowly progressive proximal muscle weakness; involvements of cardiac and/or respiratory functions are common. We describe 34 patients in nine families of FLNC-related myofibrillar myopathy in Hong Kong ethnic Chinese diagnosed over the last 12 years, in whom the same pathogenic variant c.8129G>A (p.Trp2710*) was detected. Twenty-six patients were symptomatic when diagnosed; four patients died of pneumonia and/or respiratory failure. Abnormal amorphous material or granulofilamentous masses were detected in half of the cases, with mitochondrial abnormalities noted in two-thirds. We also show by haplotype analysis the founder effect associated with this Hong Kong variant, which might have occurred 42 to 71 generations ago or around Tang and Song dynasties, and underlain a higher incidence of myofibrillar myopathy among Hong Kong Chinese. The late-onset nature and slowly progressive course of the highly penetrant condition could have significant impact on the family members, and an early diagnosis could benefit the whole family. Considering another neighboring founder variant in FLNC in German patients, we advocate development of specific therapies such as chaperone-based or antisense oligonucleotide strategies for this particular type of myopathy.

Cleaving Dihydrogen with Tetra(o-tolyl)diborane(4).

Tetra(o-tolyl)diborane(4), 1, was synthesized and characterized experimentally as well as theoretically by density functional theory (DFT) calculations. Exposure of 1 to H2 (1 bar) at room temperature afforded the corresponding di(o-tolyl)hydroborane through cleavage of the H-H and B-B bonds. DFT calculations suggested a diarylboryl anion character for the transition state.

DFT Studies of Dimerization Reactions of Boroles.

Boroles undergo dimerization reactions to give Diels-Alder (DA) dimers, bridged-bicyclic (BB) dimers or spiro dimers (SD) depending on the substituents on the borole. We performed DFT calculations to investigate how different substituents at the carbon atoms of the butadiene backbone as well as at the boron atom influence the dimerization reaction pathways. The DFT results show that, in general, both the DA and BB dimers are easily accessible kinetically, and the DA dimers are thermodynamically more stable than the BB dimers. When the substituent-substituent repulsive steric interactions are alleviated to a certain extent, the BB dimers are more stable than the DA dimer, and become accessible. The SD dimers are generally kinetically difficult to obtain. However, we found that aryl substituents promote the formation of the SD dimers.

Direct and Base-Catalyzed Diboration of Alkynes Using the Unsymmetrical Diborane(4), pinB-BMes2.

In the absence of transition metal catalysts, the unsymmetrical diborane(4), pinB-BMes2, reacted with alkynes to afford diborylalkenes. The isomer ratio of the products could be controlled via temperature, solvent, and additive(s). A reaction mechanism was proposed on the basis of two isolated intermediates, and this reaction could furthermore be applied to synthesize a luminescent molecule.

Synthesis and Characterization of Dirhenadehydro[12]annulenes.

The 12-membered-ring metallacycles [mer-Re{≡CCH=C(R)C≡C-}Cl(PMe2 Ph)3 )]2 (R=CMe3 , 1-adamantyl), which are organometallic analogues of antiaromatic octadehydro[12]annulene, are prepared by heating the methyl carbyne complexes mer-Re{≡CCH=C(R)C≡CH}(CH3 )Cl(PMe2 Ph)3 . An intermolecular σ-bond metathesis between the Re-CH3 bond and the acetylenic C-H bond is proposed for their formation.

A Potassium Diboryllithate: Synthesis, Bonding Properties, and the Deprotonation of Benzene.

A potassium diboryllithate (B2 LiK) was synthesized and structurally characterized. DFT calculations, including NPA and AIM analyses of B2 LiK, revealed ionic interactions between the two bridging boryl anions and Li(+) and K(+) . Upon standing in benzene, B2 LiK deprotonated the solvent to form a hydroborane and a phenylborane. On the basis of DFT calculations, a detailed reaction mechanism, involving deprotonation and hydride/phenyl exchange processes, is proposed. An NBO analysis of the transition state for the deprotonation of benzene suggests that the deprotonation should be induced by the coordination of benzene to the K(+) .

Lowering the reduction potential of a boron compound by means of the substituent effect of the boryl group: one-electron reduction of an unsymmetrical diborane(4).

We have clarified and observed the high electron affinity of pinB-BMes2 (1; Mes = mesityl, pin = pinacolato). By using electrochemistry, it was shown that 1 has a higher electron affinity than those of B2pin2 and Mes3B. One-electron reduction of 1 gave the corresponding radical anion. The ESR spectroscopy and DFT calculation revealed the unsymmetrical distribution of electron density over the B-B bond. UV/Vis spectroscopy showed that the SOMO-related absorption supports the deep purple color of the radical anion. DFT studies on the torsion angle dependency of the LUMO levels and relative energies revealed the reason why 1 has high electron affinity as a result of the substituent effect of the Bpin group.

Synthesis of rhenabenzenes from the reactions of rhenacyclobutadienes with ethoxyethyne.

Treatment of Na[Re(CO)5 ] with RCCCO2 Et (R=phenyl, naphthalen-1-yl, phenanthren-9-yl and pyren-1-yl) followed by reaction with acetyl chloride and ethanol afforded the rhenacyclobutadienes Re{-C(R)C(CO2 Et)C(OEt)}(CO)4 . Reactions of these rhenacyclobutadienes with HCCOEt produced rhenabenzenes Re{-C(R)C(CO2 Et)C(OEt)CHC(OEt)}(CO)4 . Except for R=Ph, new rhenacyclobutadienes with pendant alkenyl substituents Re{-C(R)C(C(OEt)CH(CO2 Et))C(OEt)}(CO)4 were also isolated from these reactions. The NMR spectroscopic and X-ray structural data, as well as the aromatic stabilization energy (ASE) values suggest that the rhenabenzenes are aromatic, with extensive delocalized π character.

Structural revision of cephalosporolide J and bassianolone.

The NMR spectra for three "natural" products: cephalosporolide C (Ces-C), cephalosporolide J (Ces-J), and bassianolone were found to be identical, and we proposed that Ces-C was the correct structure for the reported spectra. The first total synthesis of the proposed structure for Ces-J was achieved to support our structural revision for Ces-J. Chemical transformations of bassianolone and computational prediction of (13)C NMR spectra allowed us to conclude that Ces-C was the correct structure for bassianolone. Our synthetic and computational studies suggested that these "different" natural products Ces-C, Ces-J, and bassianolone have the same structure: Ces-C.

Mechanistic study on the reaction of pinB-BMes2 with alkynes based on experimental investigation and DFT calculations: gradual change of mechanism depending on the substituent.

Transition metal-free direct and base-catalyzed 1,2-diborations of arylacetylenes using pinB-BMes2 provided a syn/anti-isomeric mixture of diborylalkenes. The kinetic analysis showed that the reaction rate and isomer ratio were affected by reaction conditions and substituents on the aryl ring. DFT calculations indicated that direct addition proceeded via the interaction of acetylene-π with the BMes2 fragment. In contrast, for the base-catalyzed diboration, the previously isolated sp2-sp3 diborane and borataallene were confirmed as stable intermediates by calculations. The whole reaction pathways can be divided into the Bpin-migration and deprotonation steps, where the borataallene should be considered as a common intermediate. It should be noted that the deprotonation step is reversible and affords the kinetically less favoured isomer under the thermodynamic conditions. As a result, the composition of isomeric products, in the base-catalyzed diboration, is attributed to the small difference of activation barriers between direct and base-catalyzed systems.

Synthesis, Characterization and Electronic Structure of Dirhenadehyro[12]annulene Complexes.

Treatment of the SiMe3 -protected dichloro-rhenium carbyne complexes Re{≡CCH=C(R)C≡CSiMe3 }Cl2 (PMe2 Ph)3 (R = CMe3 , 1-adamantyl) with CsF in methanol directly afforded the 12-membered metallacycles {ReCl(PMe2 Ph)3 }2 {≡CCH=C(R)C≡C-}2 . The electronic structure of the metallacycle was investigated by density functional calculations. The UV-vis spectrum of the metallacycle shows a red-shifted band compared to that of the starting dichlorocarbyne complex. Treatment of {ReCl(PMe2 Ph)3 }2 {≡CCH=C(CMe3 )C≡C-}2 with HCl produced the dichloro-rhenium carbyne complex Re{≡CCH=C(CMe3 )C≡CH}Cl2 (PMe2 Ph)3 , which is consistent with the electronic structure of the 12-membered metallacycles.

Facile synthesis of polycyclic metallaarynes.

Metalla-analogs of polycyclic arynes represent an interesting class of metallaaromatics with a formal M[triple bond, length as m-dash]C bond within the ring. The first examples of a bicyclic ß-metallaaryne and tricyclic metallaarynes, including a metallaanthracyne and a metallaphenanthryne, were obtained in good yields by reactions of OsCl2(PPh3)3 with alkyne-functionalized phosphorus ylides.

Highly efficient tetradentate ruthenium catalyst for ester reduction: especially for hydrogenation of fatty acid esters.

A new tetradentate ruthenium complex has been developed for hydrogenation of esters. The catalyst's structure features a pyridinemethanamino group and three tight chelating five-membered rings. The structure character is believed to be responsible for its high stability and high carbonylation-resistant properties. Thus, this catalyst shows outstanding performance in the catalytic hydrogenation of a variety of esters, especially for fatty acid esters, which may be used in practical applications. New insight on designing hydrogenation catalyst for reducing esters to alcohols has been provided through theoretical calculations.

Facile scission of isonitrile carbon-nitrogen triple bond using a diborane(4) reagent.

Transition metal reagents and catalysts are generally effective to cleave all three bonds (one σ and two π) in a triple bond despite its high bonding energy. Recently, chemistry of single-bond cleavage by using main-group element compounds is rapidly being developed in the absence of transition metals. However, the cleavage of a triple bond using non-transition-metal compounds is less explored. Here we report that an unsymmetrical diborane(4) compound could react with carbon monoxide and tert-butyl isonitrile at room temperature. In the latter case, the carbon-nitrogen triple bond was completely cleaved in the absence of transition metal as confirmed by X-ray crystallographic analysis, (13)C NMR spectroscopy with (13)C labelling and DFT calculations. The DFT calculations also revealed the detailed reaction mechanism and indicated that the key for the carbon-nitrogen triple-bond cleavage could be attributed to the presence of nucleophilic nitrogen atom in one of the intermediates.

Absence of paternal accessory sex glands dysregulates preimplantation embryo cell cycle and causes early oviductal-uterine transit in the golden hamster in vivo.

We hypothesize that deletion of paternal accessory sex glands compromised developmental potential of preimplantation embryos because of dysregulation of blastomeric cell cycle regulators. Quantification by immunocytochemistry showed disrupted cyclicity of proliferating cell nuclear antigen, augmented p53 and p21 expression, and premature transit from oviduct to uterus.

Repair of infarcted myocardium by an extract of Geum japonicum with dual effects on angiogenesis and myogenesis.

BACKGROUND: It has become apparent recently that cardiac myocytes can divide after myocardial infarction, a circumstance that challenges the orthodox view that myocytes may be terminally differentiated. Replacement of the necrosed heart tissue by newly regenerated functional myocardium is a therapeutic ideal, but attempts to reconstitute functional myocardia and coronary vessels have been less successful. METHODS: We isolated a fraction containing 5 compounds from the Chinese herb Geum japonicum, which stimulates the processes of angiogenesis and cardiomyogenesis. We investigated these dual properties in both ex vivo and in vivo systems. RESULTS: We observed that this bioactive fraction displayed favorable dual actions on early angiogenesis and cardiomyogenesis in acute myocardial infarction in an animal model. Our results demonstrated that application of this bioactive fraction showed pronounced effects on limiting infarct size by 35%-45%, stimulating early development of new blood vessels in 24 h, and regenerating myocardium, replacing approximately 49% of the total infarction volume after 2 weeks. Echocardiographic studies demonstrated marked improvement of left ventricular function within 2 days after infarction, and the improvement was sustained for >1 month. CONCLUSIONS: The properties of this bioactive fraction appear to be entirely novel and represent a new approach for the treatment of ischemic heart disease.

Purification and structural characterization of the central hydrophobic domain of oleosin.

The oil bodies of rapeseeds contain a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with abundant structural alkaline proteins termed oleosins and some other minor proteins. Oleosins are unusual proteins because they contain a 70-80-residue uninterrupted nonpolar domain flanked by relatively polar C- and N-terminal domains. Although the hydrophilic N-terminal domain had been studied, the structural feature of the central hydrophobic domain remains unclear due to its high hydrophobicity. In the present study, we reported the generation, purification, and characterization of a 9-kDa central hydrophobic domain from rapeseed oleosin (19 kDa). The 9-kDa central hydrophobic domain was produced by selectively degrading the N and C termini with enzymes and then purifying the digest by SDS-PAGE and electroelution. We have also reconstituted the central domain into liposomes and synthetic oil bodies to determine the secondary structure of the domain using CD and Fourier transform infrared (FTIR) spectroscopy. The spectra obtained from CD and FTIR were analyzed with reference to structural information of the N-terminal domain and the full-length rapeseed oleosin. Both CD and FTIR analysis revealed that 50-63% of the domain was composed of beta-sheet structure. Detailed analysis of the FTIR spectra indicated that 80% of the beta-sheet structure, present in the central domain, was arranged in parallel to the intermolecular beta-sheet structure. Therefore, interactions between adjacent oleosin proteins would give rise to a stable beta-sheet structure that would extend around the surface of the seed oil bodies stabilizing them in emulsion systems. The strategies used in our present study are significant in that it could be generally used to study difficult proteins with different independent structural domains, especially with long hydrophobic domains.