A mechanism for the regioselective silaboration of terminal allene by a palladium catalyst has been studied theoretically. The overall reaction scheme has been examined in particular to determine the mechanism of the regioselectivity. The present catalytic reaction is exothermic and the rate-determining step is the insertion of allene into the Pd-B bond of the Pd complex. σ-Allylic and π-allylic complexes exist as intermediates and play an important role in the regioselectivity. Selective insertion of the unsubstituted CdC bond into the Pd-B bond produces the most stable σ-allylic complex, which converts to the π-allylic complex while maintaining the Pd-O coordination. The selective formation of the specific σ-allylic complex and the large activation barrier between two isomeric π-allylic complexes dominantly determines the regioselectivity of the present reaction. The major-product complex is less stable than the minor-product complex, and therefore kinetic control is predominant in the present reaction.

This study highlights the importance of the novel BMPR2 modifier FHIT in PH and the clinical value of the repurposed drug Enzastaurin as a potential novel therapeutic strategy to improve PAH.

Rho family small GTPases are key regulators of morphological changes in neurons. Cdc42, one of the most characterized members of the Rho family of proteins, is involved in axon and dendrite outgrowth through cytoskeletal reorganization. Recent studies have identified Zizimin1, a member of the Dock180-related family of proteins [also called CDM (Ced-5/Dock180/Myoblast city)-zizimin homology (CZH) proteins], as a specific guanine-nucleotide exchange factor (GEF) for Cdc42. However, the physiological function of Zizimin1 is totally unknown. In this study, we investigated the role of Zizimin1 in dendrite development in rat hippocampal neurons. In situ hybridization and Western blot analysis showed that Zizimin1 is strongly expressed in the developing brain including in the hippocampus and cerebral cortex in late developmental stages. Overexpression of wild-type Zizimin1 promoted dendrite growth, whereas knockdown of Zizimin1 by short hairpin RNA or expression of a mutant Zizimin1 lacking Cdc42 GEF activity suppressed dendrite growth in primary cultured rat hippocampal neurons. Both the N-terminal CZH1 domain, which is conserved among CZH proteins, and the Pleckstrin homology domain of Zizimin1 are involved in membrane localization, Cdc42 activation, and regulation of dendrite growth. Thus, these results suggest that Zizimin1 plays an important role in dendrite growth in hippocampal neurons through activation of Cdc42.

Molecular core ionization spectra and their satellites were studied by the symmetry adapted cluster-configuration interaction (SAC-CI) general-R method. The core-electron binding energies of C, N, O, and F atoms of 22 molecules were calculated with an average deviation of 0.11 eV from the experimental values. The energy splittings between K-shell gerade and ungerade states were calculated and discussed in relation to the bond length. The satellite spectra of the C 1s and N 1s core ionizations of methane and ammonia were investigated. The SAC-CI general-R method gave many shake-up states with moderate intensities, reproducing the general feature of the experimental spectra, and thus enabling the detailed understanding and assignments of the core-electron ionization spectra.

Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC50) of <1 n, and had 30–50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL–JAK2 fusion gene; IC50=11–120 n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs.