Experimental Neurology By Prof Paul Glees Pp xii + 532 (Oxford: Clarendon Press; London: Oxford University Press, 1961) 75s net

The Nervous System

The tumour suppressor p53 has a central role in the response to cellular stress. Activated p53 transcriptionally regulates hundreds of genes that are involved in multiple biological processes, including in DNA damage repair, cell cycle arrest, apoptosis and senescence. In the context of DNA damage, p53 is thought to be a decision-making transcription factor that selectively activates genes as part of specific gene expression programmes to determine cellular outcomes. In this Review, we discuss the multiple molecular mechanisms of p53 regulation and how they modulate the induction of apoptosis or cell cycle arrest following DNA damage. Specifically, we discuss how the interaction of p53 with DNA and chromatin affects gene expression, and how p53 post-translational modifications, its temporal expression dynamics and its interactions with chromatin regulators and transcription factors influence cell fate. These multiple layers of regulation enable p53 to execute cellular responses that are appropriate for specific cellular states and environmental conditions.

The multiple mechanisms that regulate p53 activity and cell fate

Dynamic Regulation of Mitochondrial Import by the Ubiquitin System.

Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways. Here, we review recent findings that advance our knowledge in epigenetic, transcriptional and metabolic regulation of adult neurogenesis in the SGZ of the hippocampus, with a special attention to the p53-family of transcription factors.

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Regulation of Adult Neurogenesis in Mammalian Brain.

Influenza A virus (IAV) has evolved various strategies to counteract the innate immune response using different viral proteins. However, the mechanism is not fully elucidated. In this study, we identified the PB1 protein of H7N9 virus as a new negative regulator of virus- or poly(I:C)-stimulated IFN induction and specifically interacted with and destabilized MAVS. A subsequent study revealed that PB1 promoted E3 ligase RNF5 to catalyze K27-linked polyubiquitination of MAVS at Lys362 and Lys461. Moreover, we found that PB1 preferentially associated with a selective autophagic receptor neighbor of BRCA1 (NBR1) that recognizes ubiquitinated MAVS and delivers it to autophagosomes for degradation. The degradation cascade mediated by PB1 facilitates H7N9 virus infection by blocking the RIG-I-MAVS-mediated innate signaling pathway. Taken together, these data uncover a negative regulatory mechanism involving the PB1-RNF5-MAVS-NBR1 axis and provide insights into an evasion strategy employed by influenza virus that involves selective autophagy and innate signaling pathways.

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The PB1 protein of influenza A virus inhibits the innate immune response by targeting MAVS for NBR1-mediated selective autophagic degradation.

Dual targeting of RIG-I and MAVS by MARCH5 mitochondria ubiquitin ligase in innate immunity.

Remodeling and spacing factor 1 (RSF1), which is one of chromatin-remodeling factors, has been linked to the DNA damage response (DDR) and DNA repair. However, the biological consequence of RSF1 deficiency in DDR in vivo and its molecular mechanisms remain unknown. Because defective DDR is related to neuropathological phenotypes, we developed neural-specific Rsf1 knockout mice. Rsf1 deficiency did not result in any neuropathological abnormalities, but prevented neural apoptosis triggered by excessive DNA strand breaks during neurogenesis. Likewise, cell death was significantly reduced in RSF1 deficient human cell lines after DNA damage, and the global transcriptome of these cells revealed that the expressions of p53 downstream genes were significantly reduced upon DNA strand breaks. Inactivation of these genes resulted from decreased binding of p53/p300 complex and subsequent reduction of H3 acetylation at their promoters. Our data show that RSF1 is necessary for p53-dependent gene expression in response to DNA strand breaks via controlling the accessibility of p53/p300 complex to its target genes and contributes to the maintenance of cellular integrity.

/pdf/chromatin-remodeling-factor-rsf1-controls-p53-mediated-2ytu0wr9ky.pdf

Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks

Sol-gel derived coating of YBCO film is very attractive for low cost as well as the ease of scalability. Among them, TFA-MOD using metal trifluoroacetates helps avoid the formation of BaCO/sub 3/ in the film. But this process has difficulties in optimizing the humid atmosphere to remove HF from the Y-Ba-Cu-O-F systems. So, in this work, another approach to chemical solution without fluorinated precursor was investigated. To make homogeneous stable solution, at first, YBCO powders were synthesized from organic solution containing Y/sub 2/O/sub 3/, BaCO/sub 3/, and CuO powders followed by calcination in air. Dip coatings were carried out from the solution of calcined YBCO powder dissolved into a mixture of methanol and propionic acid on LaAlO/sub 3/ [100] substrates. The coated film was annealed by reduced oxygen partial pressure. Dense, homogeneous and biepitaxially grown YBCO films were obtained from dip coating with /spl sim/5 mm/s of drawing speed.

New chemical route for YBCO thin films

YSZ films have been widely used as buffer layers for high T/sub c/ superconductor. However, it is necessary to investigate and develop another buffer layer with suitable, simple, and neat processing. Films of Ce-Zr mixed oxide were deposited by rf and dc magnetron co-sputtering. In sputtering process, dc power of Zr was fixed in 200 W while rf power of Ce was varied with 30 W, 50 W, 100 W, respectively. As-deposited (Ce/sub x/Zr/sub 1-x/)O/sub 2/ films were crystallized without post annealing. It was confirmed that the composition of the films could be controlled with controlling rf power of Ce target. The /spl Phi/ scan of XRD showed that all (Ce/sub x/Zr/sub 1-x/)O/sub 2/ films were [200] c-axis oriented. Three consecutive magnetron sputtering procedure for seed, CZO and cap layer for HTSC films using Ce, Zr and CeO/sub 2/ target were carried out on the Si[100] and Ni substrate successfully. It is suggested that sputtered and c-axis oriented (Ce/sub x/Zr/sub 1-x/)O/sub 2/ films can be a potential candidate to replacing YSZ buffer layer.

Characteristics of Ce-Zr mixed oxide films as buffer layer by controlling composition

Single- and multi-layer (Ce1 − xZrx)O2 films (0 ≤ x ≤ 0.84) on Si (100) and polycrystalline Ni substrates were prepared using RF and DC magnetron co-sputtering. XRD of φ scan analysis showed that all (Ce1 − xZrx)O2 films were biaxially oriented with the c-axis perpendicular to the plane of the film. During sputtering, DC power to the Zr target was fixed at 200 W, while RF power to the Ce target was set at 30 W, 50 W, or 100 W. As-deposited ZrO2 film was amorphous and was crystallized by post-annealing. However, as-deposited (Ce1 − xZrx)O2 films were crystalline even when grown at room temperature and the structures of films were cubic or tetragonal depending on the Ce ion incorporation. It was found that multilayered CeO2/(Ce1 − xZrx)O2/CeO2 films could be deposited with a continuous compositional gradient in a sputtering batch. This layered CeO2/CZO/CeO2 structure can maintain its original texture after 800°C annealing and is therefore suitable for subsequent YBCO film growth. Furthermore, Ni diffusion is effectively blocked by the buffer layers just like the YSZ currently used in coated conductor fabrication.

S.I. Kim

Papers

Dual targeting of RIG-I and MAVS by MARCH5 mitochondria ubiquitin ligase in innate immunity.

Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks

New chemical route for YBCO thin films

Characteristics of Ce-Zr mixed oxide films as buffer layer by controlling composition

Characteristics of Textured Ce-Zr Mixed-Oxide Films as Buffer Layer for YBCO Coated Conductors