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RNAi Screening in Drosophila Cells Identifies New Modifiers of Mutant Huntingtin Aggregation
Joanna Doumanis, Koji Wada, Yoshihiro Kino, Adrian W. Moore, Nobuyuki Nukina
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007275
Abstract: The fruitfly Drosophila melanogaster is well established as a model system in the study of human neurodegenerative diseases. Utilizing RNAi, we have carried out a high-throughput screen for modifiers of aggregate formation in Drosophila larval CNS-derived cells expressing mutant human Huntingtin exon 1 fused to EGFP with an expanded polyglutamine repeat (62Q). 7200 genes, encompassing around 50% of the Drosophila genome, were screened, resulting in the identification of 404 candidates that either suppress or enhance aggregation. These candidates were subjected to secondary screening in normal length (18Q)-expressing cells and pruned to remove dsRNAs with greater than 10 off-target effects (OTEs). De novo RNAi probes were designed and synthesized for the remaining 68 candidates. Following a tertiary round of screening, 21 high confidence candidates were analyzed in vivo for their ability to modify mutant Huntingtin-induced eye degeneration and brain aggregation. We have established useful models for the study of human HD using the fly, and through our RNAi screen, we have identified new modifiers of mutant human Huntingtin aggregation and aggregate formation in the brain. Newly identified modifiers including genes related to nuclear transport, nucleotide processes, and signaling, may be involved in polyglutamine aggregate formation and Huntington disease cascades.
Loss of aPKCλ in Differentiated Neurons Disrupts the Polarity Complex but Does Not Induce Obvious Neuronal Loss or Disorientation in Mouse Brains
Tomoyuki Yamanaka, Asako Tosaki, Masaru Kurosawa, Kazunori Akimoto, Tomonori Hirose, Shigeo Ohno, Nobutaka Hattori, Nobuyuki Nukina
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084036
Abstract: Cell polarity plays a critical role in neuronal differentiation during development of the central nervous system (CNS). Recent studies have established the significance of atypical protein kinase C (aPKC) and its interacting partners, which include PAR-3, PAR-6 and Lgl, in regulating cell polarization during neuronal differentiation. However, their roles in neuronal maintenance after CNS development remain unclear. Here we performed conditional deletion of aPKCλ, a major aPKC isoform in the brain, in differentiated neurons of mice by camk2a-cre or synapsinI-cre mediated gene targeting. We found significant reduction of aPKCλ and total aPKCs in the adult mouse brains. The aPKCλ deletion also reduced PAR-6β, possibly by its destabilization, whereas expression of other related proteins such as PAR-3 and Lgl-1 was unaffected. Biochemical analyses suggested that a significant fraction of aPKCλ formed a protein complex with PAR-6β and Lgl-1 in the brain lysates, which was disrupted by the aPKCλ deletion. Notably, the aPKCλ deletion mice did not show apparent cell loss/degeneration in the brain. In addition, neuronal orientation/distribution seemed to be unaffected. Thus, despite the polarity complex disruption, neuronal deletion of aPKCλ does not induce obvious cell loss or disorientation in mouse brains after cell differentiation.
Large-Scale RNA Interference Screening in Mammalian Cells Identifies Novel Regulators of Mutant Huntingtin Aggregation
Tomoyuki Yamanaka, Hon Kit Wong, Asako Tosaki, Peter O. Bauer, Koji Wada, Masaru Kurosawa, Tomomi Shimogori, Nobutaka Hattori, Nobuyuki Nukina
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093891
Abstract: In polyglutamine (polyQ) diseases including Huntington's disease (HD), mutant proteins containing expanded polyQ stretch form aggregates in neurons. Genetic or RNAi screenings in yeast, C. elegans or Drosophila have identified multiple genes modifying polyQ aggregation, a few of which are confirmed effective in mammals. However, the overall molecular mechanism underlying polyQ protein aggregation in mammalian cells still remains obscure. We here perform RNAi screening in mouse neuro2a cells to identify mammalian modifiers for aggregation of mutant huntingtin, a causative protein of HD. By systematic cell transfection and automated cell image analysis, we screen ~12000 shRNA clones and identify 111 shRNAs that either suppress or enhance mutant huntingtin aggregation, without altering its gene expression. Classification of the shRNA-targets suggests that genes with various cellular functions such as gene transcription and protein phosphorylation are involved in modifying the aggregation. Subsequent analysis suggests that, in addition to the aggregation-modifiers sensitive to proteasome inhibition, some of them, such as a transcription factor Tcf20, and kinases Csnk1d and Pik3c2a, are insensitive to it. As for Tcf20, which contains polyQ stretches at N-terminus, its binding to mutant huntingtin aggregates is observed in neuro2a cells and in HD model mouse neurons. Notably, except Pik3c2a, the rest of the modifiers identified here are novel. Thus, our first large-scale RNAi screening in mammalian system identifies previously undescribed genetic players that regulate mutant huntingtin aggregation by several, possibly mammalian-specific mechanisms.
Phosphorylation of Mitochondrial Polyubiquitin by PINK1 Promotes Parkin Mitochondrial Tethering
Kahori Shiba-Fukushima,Taku Arano,Gen Matsumoto,Tsuyoshi Inoshita,Shigeharu Yoshida,Yasushi Ishihama,Kwon-Yul Ryu,Nobuyuki Nukina,Nobutaka Hattori ,Yuzuru Imai
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004861
Abstract: The kinase PINK1 and the E3 ubiquitin (Ub) ligase Parkin participate in mitochondrial quality control. The phosphorylation of Ser65 in Parkin's ubiquitin-like (UBl) domain by PINK1 stimulates Parkin activation and translocation to damaged mitochondria, which induces mitophagy generating polyUb chain. However, Parkin Ser65 phosphorylation is insufficient for Parkin mitochondrial translocation. Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. The expression of Tom70MTS-4xUb SE, which mimics phospho-Ser65 polyUb chains on the mitochondria, activated Parkin E3 activity and its mitochondrial translocation. An E3-dead form of Parkin translocated to mitochondria with reduced membrane potential in the presence of Tom70MTS-4xUb SE, whereas non-phospho-polyUb mutant Tom70MTS-4xUb SA abrogated Parkin translocation. Parkin binds to the phospho-polyUb chain through its RING1-In-Between-RING (IBR) domains, but its RING0-linker is also required for mitochondrial translocation. Moreover, the expression of Tom70MTS-4xUb SE improved mitochondrial degeneration in PINK1-deficient, but not Parkin-deficient, Drosophila. Our study suggests that the phosphorylation of mitochondrial polyUb by PINK1 is implicated in both Parkin activation and mitochondrial translocation, predicting a chain reaction mechanism of mitochondrial phospho-polyUb production by which rapid translocation of Parkin is achieved.
Georgiana Cristina NUKINA
Revista Roman? de Statistic? , 2012,
Abstract: Through Risk analysis developed model deciding whether control measures suitable for implementation. However, the analysis determines whether the benefits of a data control options cost more than the implementation.
A C-Based Variable Length and Vector Pipeline Architecture Design Methodology and Its Application  [PDF]
Takashi Kambe, Nobuyuki Araki
Circuits and Systems (CS) , 2012, DOI: 10.4236/cs.2012.31002
Abstract: The size and performance of a System LSI depend heavily on the architecture which is chosen. As a result, the architecture design phase is one of the most important steps in the System LSI development process and is critical to the commercial success of a device. In this paper, we propose a C-based variable length and vector pipeline (VVP) architecture design methodology and apply it to the design of the output probability computation circuit for a speech recognition system. VVP processing accelerated by loop optimization, memory access methods, and application-specific cir- cuit design was implemented to calculate the Hidden Markov Model (HMM) output probability at high speed and its performance is evaluated. It is shown that designers can explore a wide range of design choices and generate complex circuits in a short time by using a C-based pipeline architecture design method.
Sound Source Measurement of a Semi-Circular Cylinder in a Uniform Flow by Particle Image Velocimetry  [PDF]
Yasuyuki Oguma, Nobuyuki Fujisawa
Journal of Flow Control, Measurement & Visualization (JFCMV) , 2016, DOI: 10.4236/jfcmv.2016.44014
Abstract: In this paper, the measurement of an aerodynamic sound source for a semi-circular cylinder in a uniform flow is described using Particle Image Velocimetry (PIV). This experimental technique is based on vortex sound theory, where the time derivative of vorticity is evaluated with the aid of two sets of standard PIV systems. The experimental results indicate that the sound source for the semi-circular cylinder is located around the shear layer near the edge of the semi-circular cylinder. The sound source intensity and the area are reduced in the semi-circular cylinder compared with those of a circular cylinder. This result indicates that the aerodynamic sound of the semi- circular cylinder is smaller than that of the circular cylinder, which supports the microphone measurement result.
The Effect of Monocular Blur on the Binocular Visual Field  [PDF]
Fusako Fujimura, Nobuyuki Shoji
Open Journal of Ophthalmology (OJOph) , 2018, DOI: 10.4236/ojoph.2018.81002
Purpose/Aim: We aimed to investigate the effect of monocular blur on the binocular visual field. Materials and Methods: A total of 13 healthy young volunteers participated in this study. The mean subjective refractive error of the dominant eye (DE) was -3.33 ± 1.65D, and the non-dominant eye (NDE) was -3.15 ± 2.84D. The DE was determined by using the hole-in-the-card test. The visual field was examined by the Humphrey Visual Field Analyzer using the 30-2 SITA Standard program. The visual field was measured while wearing soft contact lens under three conditions; ① both eyes: near vision correction; ② DE: near vision correction +3.00D added, NDE: near vision correction; and ③ DE: near vision correction, NDE: near vision correction +3.00D added. The foveal threshold, mean deviation (MD), and pattern standard deviation (PSD) values were investigated. Results: The foveal threshold value (dB) at ①, ②, and ③ was 41.2, 37.8, and 38.1, respectively. The values at ② and ③ were both significantly lower than that at ① (p < 0.0001; p = 0.0003). The MD value (dB) at ①, ②, and ③ was 1.67, 0.19, and 0.51, respectively; the values at ② and ③ were both significantly lower than that at ① (p = 0.0012; p = 0.0118). The PSD value (dB) at ①, ②, and ③ was 1.36, 1.55, and 1.47, respectively. A significant difference in ①, ②, and ③ was not found. Conclusion: These results suggest that monocular blur reduced the sensitivity within the binocular visual field.
Effect of Rotation and Revolution on Performance of Blade-Free Planetary Mixer  [PDF]
Takayuki Yamagata, Nobuyuki Fujisawa
Journal of Flow Control, Measurement & Visualization (JFCMV) , 2019, DOI: 10.4236/jfcmv.2019.71001
Abstract: In this study, flow structures and mixing performance in a blade-free planetary mixer, which combines rotation and revolution motions inside a cylindrical vessel, are numerically investigated. Flow fields in the mixer vessel are simulated in a single rotating reference frame with various revolution speeds and a fixed rotation speed. The mixing process is investigated by a Lagrangian particle tracking method and the mixing performance is evaluated based on particle concentration. The results of the numerical simulations show that a vortical flow with an axis inclined with respect to the rotation axis of the vessel is generated by the combined influence of the rotation and revolution motions. The flow structure and vortical flow intensity vary as a function of the precession rate, which is the ratio of the revolution speed to rotation speed. The mixing performance of the blade-free planetary mixer is found to be maximum at aspecific precession rate.
Childhood physical abuse in outpatients with psychosomatic symptoms
Masanori Handa, Hideyuki Nukina, Masako Hosoi, Chiharu Kubo
BioPsychoSocial Medicine , 2008, DOI: 10.1186/1751-0759-2-8
Abstract: We divided 564 consecutive new outpatients at the Department of Psychosomatic Medicine of Kyushu University Hospital into two groups: a physically abused group and a non-abused group. Psychological test scores and the prevalence of self-injurious behavior were compared between the two groups.A history of childhood physical abuse was reported by patients with depressive disorders(12.7%), anxiety disorders(16.7%), eating disorders (16.3%), pain disorders (10.8%), irritable bowel syndrome (12.5%), and functional dyspepsia(7.5%). In both the patients with depressive disorders and those with anxiety disorders, STAI-I (state anxiety) and STAI-II (trait anxiety) were higher in the abused group than in the non-abused group (p < 0.05).In the patients with depressive disorders, the abused group was younger than the non-abused group (p < 0.05). The prevalence of self-injurious behavior of the patients with depressive disorders, anxiety disorders and pain disorders was higher in the abused groups than in the non-abused groups (p < 0.005).A history of childhood physical abuse is associated with psychological distress such as anxiety, depression and self-injurious behavior in outpatients with psychosomatic symptoms. It is important for physicians to consider the history of abuse in the primary care of these patients.Reports of abuse and domestic violence have been increasing in Japan. However, few studies have been done of the prevalence of physical or sexual abuse history in Japan and Asia. In a large, national telephone survey of 1,145 men and 1,481 women in the United States, Finkelhor et al. reported the prevalence of child sexual abuse history to be 27% for women and 16% for men [1]. The American rate of physical abuse history has been estimated at 5.7 cases per 1000 children [2]. Drossman and Leserman reported a high prevalence of sexual and physical abuse history among female outpatients referred to a gastroenterology clinic [3]. They found that 44% of the studied women re
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