Neuronal cell death, abnormal protein aggregates, and cytoplasmic vacuolization are major pathologies observed in many neurodegenerative disorders such as the polyglutamine (polyQ) diseases, prion ...disease, Alzheimer disease, and the Lewy body diseases, suggesting common mechanisms underlying neurodegeneration. Here, we have identified VCP/p97, a member of the AAA+ family of ATPase proteins, as a polyQ-interacting protein in vitro and in vivo, and report on its characterization. Endogenous VCP co-localized with expanded polyQ (ex-polyQ) aggregates in cultured cells expressing ex-polyQ, with nuclear inclusions in Huntington disease patient brains, and with Lewy bodies in patient samples. Moreover, the expression of VCP mutants with mutations in the 2nd ATP binding domain created cytoplasmic vacuoles, followed by cell death. Very similar vacuoles were also induced by ex-polyQ expression or proteasome inhibitor treatment. These results suggest that VCP functions not only as a recognition factor for abnormally folded proteins but also as a pathological effector for several neurodegenerative phenotypes. VCP may thus be an ideal molecular target for the treatment of neurodegenerative disorders.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We evaluated the circadian phenotypes of patients with delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders ...(CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.
In this study, the roles of p53 in impaired spermatogenic male germ cells of p53-deficient medaka were investigated by analyzing histological changes, and gene expressions of 42Sp50, Oct 4 and ...vitellogenin (VTG2) by RT-PCR or in situ hybridization in the testes. We found that a small number of oocyte-like cells (testis-ova) differentiated spontaneously in the cysts of type A and early type B spermatogonia in the p53-deficient testes, in contrast to the wild-type (wt) testes in which testis-ova were never found. Furthermore, ionizing radiation (IR) irradiation increased the number of testis-ova in p53-deficient testes, increased testis-ova size and proceeded up to the zygotene or pachytene stages of premature meiosis within 14 days after irradiation. However, 28 days after irradiation, almost all the testis-ova were eliminated presumably by p53-independent apoptosis, and spermatogenesis was restored completely. In the wt testis, IR never induced testis-ova differentiation. This is the first study to demonstrate the pivotal role of the p53 gene in the elimination of spontaneous testis-ova in testes, and that p53 is not indispensable for the restoration of spermatogenesis in the impaired testes in which cell cycle regulation is disturbed by IR irradiation.
We previously found that the methanol extract of a marine brown alga,
Sargassum macrocarpum showed marked nerve growth factor (NGF)-dependent neurite outgrowth promoting activity to PC12D cells. The ...active substance purified was elucidated to be sargachromenol. The median effective dose (ED50) was 9 μM against PC12D cells in the presence of 10 ng/ml NGF, although it showed no neurotrophic effect on its own. Pretreatment of cells with protein kinase A (PKA) inhibitor or U0126 substantially suppressed the sargachromenol-enhanced neurite outgrowth from PC12D cells, suggesting that the activation of cyclic AMP-mediated protein kinase and mitogen-activated protein (MAP) kinase 1/2 was apparently required for the action of sargachromenol. On the other hand, sargachromenol significantly promoted the survival of neuronal PC12D cells at 0–50 ng/ml NGF in serum-free medium. Neither PKA inhibitor nor U0126 could inhibit the survival supporting effect of sargachromenol, whereas wortmannin significantly blocked the sargachromenol-induced survival supporting effect on neuronal PC12D cells, suggesting that sargachromenol rescued neuronal PC12D cells by activating phosphatidylinositol-3 kinase. These results demonstrate that sargachromenol promotes neuronal differentiation of PC12D cells and supports the survival of neuronal PC12D cells via two distinct signaling pathways.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We screened in vitro antiviral activity against a salmonid pathogenic virus, infectious hematopoietic necrosis virus (IHNV), from the extracts of a total of 342 species of marine algae collected from ...the Japanese coastline. The anti-IHNV activity was found primarily in MeOH extracts, and the extract from one marine brown alga in particular, Eisenia bicyclis, showed high anti-IHNV activity. The anti-IHNV compound was isolated and purified as MC15 from the E. bicyclis extract, and the chemical structure was determined by several spectrometric analyses. The antiviral compound was proved to be a chlorophyll c2 derivative lacking the metal ion Mg²⁺. MC15 showed similar antiviral activity against other salmonid enveloped viruses such as Paralichthys olivaceus virus and Oncorhynchus masou virus, and stability against any pH and temperatures up to 100 °C. No cytotoxicity was observed at up to 5 μg/ml. The antiviral mechanism of MC15 appears to be direct inactivation of the viral particles. A time course study showed that the inactivation of IHNV was completed within 40 min when 200 PFU of IHNV was reacted with MC15 at 800 ng/ml.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We present two results of a search for MeV-scale neutrino and anti-neutrino events correlated with gravitational wave events/candidates and large solar flares with KamLAND. The KamLAND detector is a ...large-volume neutrino detector using liquid scintillator, which is located at 1 km underground under the top of Mt. Ikenoyama in Kamioka, Japan. KamLAND has multiple reaction channels to detect neutrinos. Electron antineutrino can be detected via inverse-beta decay with 1.8 MeV neutrino energy threshold. All flavors of neutrinos can be detected via neutrino-electron scattering without neutrino energy threshold. KamLAND has continued the neutrino observation since 2002 March. We use the data set of 60 gravitational waves provided by the LIGO/Virgo collaboration during their second and third observing runs and search for coincident electron antineutrino events in KamLAND. We find no significant coincident signals within a ±500 s timing window from each gravitational wave and present 90% C.L. upper limits on the electron antineutrino fluence between 108–1013 cm-2 for neutrino energies of 1.8–111 MeV. For a solar-flare neutrino search at KamLAND, we determine the timing window using the solar X-ray data set provided by the GOES satellite series from 2002 to 2019 and search for the excess of coincident event rate on the all-flavor neutrinos. We find no significant event rate excess in the flare time windows and get 90% C.L. upper limits on the fluence of neutrinos of all flavors (electron anti-neutrinos) between 1010–1013 cm-2 (108–1013 cm-2) for neutrino energies in the energy range of 0.4–35 MeV.
Thyroid-hormone and retinoic-acid receptors exert their regulatory functions by acting as both activators and repressors of gene expression. A nuclear receptor co-repressor (N-CoR) of relative ...molecular mass 270K has been identified which mediates ligand-independent inhibition of gene transcription by these receptors, suggesting that the molecular mechanisms of repression by thyroid-hormone and retinoic-acid receptors are analogous to the co-repressor-dependent transcriptional inhibitory mechanisms of yeast and Drosophila.
Defect prediction models are a well-known technique for identifying defect-prone files or packages such that practitioners can allocate their quality assurance efforts (e.g., testing and code ...reviews). However, once the critical files or packages have been identified, developers still need to spend considerable time drilling down to the functions or even code snippets that should be reviewed or tested. This makes the approach too time consuming and impractical for large software systems. Instead, we consider defect prediction models that focus on identifying defect-prone ("risky") software changes instead of files or packages. We refer to this type of quality assurance activity as "Just-In-Time Quality Assurance," because developers can review and test these risky changes while they are still fresh in their minds (i.e., at check-in time). To build a change risk model, we use a wide range of factors based on the characteristics of a software change, such as the number of added lines, and developer experience. A large-scale study of six open source and five commercial projects from multiple domains shows that our models can predict whether or not a change will lead to a defect with an average accuracy of 68 percent and an average recall of 64 percent. Furthermore, when considering the effort needed to review changes, we find that using only 20 percent of the effort it would take to inspect all changes, we can identify 35 percent of all defect-inducing changes. Our findings indicate that "Just-In-Time Quality Assurance" may provide an effort-reducing way to focus on the most risky changes and thus reduce the costs of developing high-quality software.
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