Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multi-stage, systems biology approach to elucidate disease mechanisms in frontotemporal dementia (FTD). We identify two gene co-expression modules that are preserved in mice harboring mutations in MAPT, GRN, and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory miRNA module, re-capitulates mRNA co-expression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species, network approach to drug discovery.

In its element: Zn(2+) at the M7 site of MFI-type zeolites activates H(2), via ZnH and OH species, and leads to Zn(0) species. The Zn(0) species returns to its original state, a Zn(2+) ion, upon evacuation of the zeolite at 873 K (see picture). The formation of the Zn(0) species is supported by DFT calculations.

Although a terminal oxyl species bound to certain metal ions is believed to be the intermediate for various oxidation reactions, such as O-O bond generation in photosystem II (PSII), such systems have not been characterized. Herein, we report a stable Zn -oxyl species induced by an MFI-type zeolite lattice and its reversible reactivity with O at room temperature. Its intriguing characteristics were confirmed by in situ spectroscopic studies in combination with quantum-chemical calculations, namely analyses of the vibronic Franck-Condon progressions and the ESR signal features of both Zn -oxyl and Zn -ozonide species formed during this reversible process. Molecular orbital analyses revealed that the reversible reaction between a Zn -oxyl species and an O molecule proceeds via a radical O-O coupling-decoupling mechanism; the unpaired electron of the oxyl species plays a pivotal role in the O-O bond generation process.

In this work, we used both experimental and density functional theory (DFT) calculation methods to examine the mechanism of CH 4 activation taking place on the Zn 2+ ion exchanged MFI-type zeolite (ZnMFI). The heterolytic dissociation of CH 4 on ZnMFI around 300 K was observed experimentally, causing the appearance of IR bands at 3615, 2930, and 2892 cm −1 . The first band can be assigned to the OH stretching vibration associated with the formation of the Brønsted acid site and the latter to the C−H stretching modes ascribable to the −[ZnCH 3 ] + species. Combining the IR spectroscopy with a DFT calculation, it is apparent that the heterolytic C−H bond dissociation of CH 4 has an activation energy of 15 kJ mol −1 and takes place on a monomeric Zn 2+ at the M7S2 site. The M7S2 site has a specific Al arrangement in MFI and exhibits a pronounced reactivity for the H−H bond cleavage of H 2 , even at room temperature. In addition, to our knowledge, we are the first to succeed in explaining the dissociation process of CH 4 by applying natural bond orbital (NBO) and interaction localized orbital (ILO) analyses to the present system; the donation interaction from the CH 4 −σ(C−H) orbital to the Zn−4s orbital triggers the cleavage of the C−H bond of CH 4 under mild conditions.

For the first time, the paramagnetic Zn(+) species was prepared successfully by the excitation with ultraviolet light in the region ascribed to the absorption band resulting from the 4s-4p transition of an atomic Zn(0) species encapsulated in an MFI-type zeolite. The formed species gives a specific electron spin resonance band at g = 1.998 and also peculiar absorption bands around 38,000 and 32,500 cm(-1) which originate from 4s-4p transitions due to the Zn(+) species with paramagnetic nature that is formed in MFI. The transformation process (Zn(0) → Zn(+)) was explained by considering the mechanism via the excited triplet state ((3)P) caused by the intersystem crossing from the excited singlet state ((1)P) produced through the excitation of the 4s-4p transition of an atomic Zn(0) species grafted in MFI by UV light. The transformation process was well reproduced with the aid of a density functional theory calculation. The thus-formed Zn(+) species which has the doublet spin state exhibits characteristic reaction nature at room temperature for an O2 molecule having a triplet spin state in the ground state, forming an η(1) type of Zn(2+)-O2(-) species. These features clearly indicate the peculiar reactivity of Zn(+) in MFI, whereas Zn(0)-(H(+))2MFI hardly reacts with O2 at room temperature. The bonding nature of [Zn(2+)-O2(-)] species was also evidenced by ESR measurements and was also discussed on the basis of the results obtained through DFT calculations.