Tetra(n-butyl)ammonium salt of a ferrimagnetic complex based on mixed-valent dinuclear ruthenium pivalate and octacyanidotungstate(V)

International audienceA tetra (n-butyl)ammonium (n-Bu4N+) salt of Ru2–W complex consisting of dinuclear ruthenium (II,III) pivalate, ([RuIIRuIII(piv)4]+) (Hpiv = pivalic acid), and octacyanidotungstate(V), [n-Bu4N][{RuIIRuIII(piv)4}2(H2O){WV(CN)8}] (1), was synthesized and characterized by elemental analysis, infrared spectra, and temperature dependence of magnetic susceptibilities (2–300 K). The crystal structure of 1 revealed a zigzag one-dimensional chain molecule along the c axis with alternating arrangement of [RuIIRuIII(piv)4]+ and [WV(CN)8]3−, where another [RuIIRuIII(piv)4]+ unit is dangled from the [WV(CN)8]3− moiety. The magnetic susceptibilities and zero-field-cooled and field-cooled magnetization data showed that the present complex is ferrimagnetic with a Tc value of 5.5 K. The field dependence of magnetization exhibited a hysteresis with a coercive field of 150 Oe at 2 K

Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme

Mutations in chromatin modifier genes are frequently associated with neurodevelopmental diseases. We herein demonstrate that the chromodomain helicase DNA-binding protein 7 (Chd7), frequently associated with CHARGE syndrome, is indispensable for normal cerebellar development. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors leads to cerebellar hypoplasia in mice, due to the impairment of granule neuron differentiation, induction of apoptosis and abnormal localization of Purkinje cells, which closely recapitulates known clinical features in the cerebella of CHARGE patients. Combinatory molecular analyses reveal that Chd7 is required for the maintenance of open chromatin and thus activation of genes essential for granule neuron differentiation. We further demonstrate that both Chd7 and Top2b are necessary for the transcription of a set of long neuronal genes in cerebellar granule neurons. Altogether, our comprehensive analyses reveal a mechanism with chromatin remodellers governing brain development via controlling a core transcriptional programme for cell-specific differentiation.Spanish Government SAF2010-21017, SAF2013-47343-P, SAF2014-55532-RAndalusian Regional Government P11-CVI-794

Infrequent RAS mutation is not associated with specific histological phenotype in gliomas

BACKGROUND: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. METHODS: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. RESULTS: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. CONCLUSION: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma

<i>MYCN</i> amplification drives an aggressive form of spinal ependymoma

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification

ZFTA-RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Over 60% of supratentorial (ST) ependymomas harbor a ZFTA-RELA (ZRfus) gene fusion (formerly C11orf95-RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE driven ZRfus tumors by CUT&RUN, ChIP, ATAC, and RNA sequencing and compared to human ZRfus driven ependymoma. In addition to direct canonical NF-κB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with Plagl family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional co-activators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by Plagl transcription factor proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks

様々な物質とペプチドの複合体におけるナノ・バイオへの応用展開の検討

研究目的：近年、機能性中分子として注目されているペプチド （小タンパク質 を、さらに高機能化、多機能化させることを指向して、生体分子、無機化合物、有機小分子、高分子などと複合させた新規機能性複合体の創製を目的とする。また、これら複合体を用いたナノ分野やバイオ分野への応用展開の検討も行う 。研究概要：これまで分子単体では達成できなかったような高機能・多機能性の材料開発を目指し、無機化合物、有機小分子、高分子とペプチドを複合させた新規機能性複合体を創製する。その創製に際しては、近年、機能性中分子として注目されているペプチドを基に、ある機能を有するペプチドに、糖、核酸、酵素などの生体分子、有機合成小分子、合成高分子、無機化合物などをそれらと結合するペプチドリガンドを介して あるいは共有結合などで 複合させることで、従来以上 に 高機能化、多機能化 させた分子・複合体の創製 をねらう。さらに、本研究で作製できた複合体を用 いて、多段階触媒能を有する材料や、エレクトロニクス材料、特定疾病分子などを高度に検出できる素子、治療に役立つ薬剤などの開発につなげ、ナノ分野、バイオ分野への工学的な応用展開を検討する