Multiple Controls Regulate Nucleostemin Partitioning Between Nucleolus and Nucleoplasm

Nucleostemin plays an essential role in maintaining the continuous proliferation of stem cells and cancer cells. The movement of nucleostemin between the nucleolus and the nucleoplasm provides a dynamic way to partition the nucleostemin protein between these two compartments. Here, we showed that nucleostemin contained two nucleolus-targeting regions, the basic and the GTP-binding domains, which exhibited a short and a long nucleolar retention time, respectively. In a GTP-unbound state, the nucleolus-targeting activity of nucleostemin was blocked by a mechanism that trapped its intermediate domain in the nucleoplasm. A nucleostemin-interacting protein, RSL1D1, was identified that contained a ribosomal L1-domain, co-resided with nucleostemin in the same subnucleolar compartment non-identical to the B23 and fibrillarin distributions, and displayed a longer nucleolar residence time than nucleostemin. RSL1D1 interacted with both the basic and the GTP-binding domains of nucleostemin through a non-nucleolus-targeting region. Overexpression of the nucleolus-targeting domain of RSL1D1 alone dispersed the nucleolar nucleostemin. Loss of RSL1D1 expression reduced the compartmental size and amount of nucleostemin in the nucleolus. This work reveals that the partitioning of nucleostemin employs complex mechanisms involving both nucleolar and nucleoplasmic components, and provides insight into the post-translational regulation of its activity

A multistep, GTP-driven mechanism controlling the dynamic cycling of nucleostemin

Nucleostemin (NS) was identified as a stem cell– and cancer cell–enriched nucleolar protein that controls the proliferation of these cells. Here, we report the mechanism that regulates its dynamic shuttling between the nucleolus and nucleoplasm. The nucleolar residence of nucleostemin involves a transient and a long-term binding by the basic and GTP-binding domains, and a dissociation mechanism mediated by the COOH-terminal region. This cycle is propelled by the GTP binding state of nucleostemin. We propose that a rapid nucleostemin cycle is designed to translate extra- and intra-cellular signals into the amount of nucleostemin in the nucleolus in a bidirectional and fast manner

Analysis and Development of Emergency Management Information System for Railway Systems in Taiwan

Railway is one of the most efficient, convenient, and comfortable ways with maximum mobility to meet people. Railway accidents or disasters often cause delays and service interruptions, resulting in operational and other loss. Despite many railway systems in Taiwan having a variety of monitoring systems for natural disasters, they still need an efficient platform for the emergency management of disasters and accidents since time and efficiency are the keys to emergency management. This study aims to fill in this gap by developing an emergency management information system for Railway Systems in Taiwan, i.e. “Railway Emergency Management Information System”, to support railway emergency management center and its sub-divisions in resource management, communication, messaging, and information sharing among different groups. The system includes many features that will improve communications between emergency management center and the mobile emergency management center to facilitate the progress of the disaster control units and dispatching at the disaster site. The study’s information system has been designated by local railway administration as the core system and starts trial since February 2012. Information requirement analysis, framework and design of the aforementioned information system will be discussed in this paper. It is hoped that the present study's information system research will help improve the emergency response of railway administration and provide safer rail transport service for the passengers

Optimal maintenance time for imperfect maintenance actions on repairable product

[[abstract]]This paper develops a maintenance strategy for repairable products that combines imperfect maintenance actions at pre-scheduled times and minimal repair actions for failures. Under a power law process of failures, an expected total cost is developed that involves the sum of the total cost of imperfect preventive maintenances and the expected total cost of minimal repairs. Moreover, a searching procedure is provided to determine the optimal maintenance schedule within a finite time span of warranty. When the parameters of the power law process are unknown, the accuracy of the estimated maintenance schedule is evaluated based on data through an asymptotic upper bound for the difference of the true expected total cost and its estimate. The proposed method is applied to an example regarding the maintenance of power transformers and the performance of the proposed method is investigated through a numerical study. Numerical results show that the proposed maintenance strategy could save cost whether an imperfect maintenance action or the perfect maintenance action is implemented.[[journaltype]]國外[[incitationindex]]SCI[[booktype]]紙本[[countrycodes]]GB

Interleukin-13 Genetic Variants, Household Carpet Use and Childhood Asthma

10.1371/journal.pone.0051970PLoS ONE81

A quantitative risk assessment model to evaluate effective border control measures for rabies prevention

Border control is the primary method to prevent rabies emergence. This study developed a quantitative risk model incorporating stochastic processes to evaluate whether border control measures could efficiently prevent rabies introduction through importation of cats and dogs using Taiwan as an example. Both legal importation and illegal smuggling were investigated. The impacts of reduced quarantine and/or waiting period on the risk of rabies introduction were also evaluated. The results showed that Taiwan's current animal importation policy could effectively prevent rabies introduction through legal importation of cats and dogs. The median risk of a rabid animal to penetrate current border control measures and enter Taiwan was 5.33 X 10(-8) (95th percentile: 3.20 x 10(-7)). However, illegal smuggling may pose Taiwan to the great risk of rabies emergence. Reduction of quarantine and/or waiting period would affect the risk differently, depending on the applied assumptions, such as increased vaccination coverage, enforced custom checking, and/or change in number of legal importations. Although the changes in the estimated risk under the assumed alternatives were not substantial except for completely abolishing quarantine, the consequences of rabies introduction may yet be considered to be significant in a rabies-free area. Therefore, a comprehensive benefit-cost analysis needs to be conducted before recommending these alternative measures

Histone deacetylase 11 inhibition promotes breast cancer metastasis from lymph nodes

Lymph node (LN) metastases correspond with a worse prognosis in nearly all cancers, yet the occurrence of cancer spreading from LNs remains controversial. Additionally, the mechanisms explaining how cancers survive and exit LNs are largely unknown. Here, we show that breast cancer patients frequently have LN metastases that closely resemble distant metastases. In addition, using a microsurgical model, we show how LN metastasis development and dissemination is regulated by the expression of a chromatin modifier, histone deacetylase 11 (HDAC11). Genetic and pharmacologic blockade of HDAC11 decreases LN tumor growth, yet substantially increases migration and distant metastasis formation. Collectively, we reveal a mechanism explaining how HDAC11 plasticity promotes breast cancer growth as well as dissemination from LNs and suggest caution with the use of HDAC inhibitors

GNL3L stabilizes the TRF1 complex and promotes mitotic transition

Telomeric repeat binding factor 1 (TRF1) is a component of the multiprotein complex “shelterin,” which organizes the telomere into a high-order structure. TRF1 knockout embryos suffer from severe growth defects without apparent telomere dysfunction, suggesting an obligatory role for TRF1 in cell cycle control. To date, the mechanism regulating the mitotic increase in TRF1 protein expression and its function in mitosis remains unclear. Here, we identify guanine nucleotide-binding protein-like 3 (GNL3L), a GTP-binding protein most similar to nucleostemin, as a novel TRF1-interacting protein in vivo. GNL3L binds TRF1 in the nucleoplasm and is capable of promoting the homodimerization and telomeric association of TRF1, preventing promyelocytic leukemia body recruitment of telomere-bound TRF1, and stabilizing TRF1 protein by inhibiting its ubiquitylation and binding to FBX4, an E3 ubiquitin ligase for TRF1. Most importantly, the TRF1 protein-stabilizing activity of GNL3L mediates the mitotic increase of TRF1 protein and promotes the metaphase-to-anaphase transition. This work reveals novel aspects of TRF1 modulation by GNL3L

Acute anal stretch inhibits NMDA-dependent pelvic-urethra reflex potentiation via spinal GABAergic inhibition in anesthetized rats

The impact of acute anal stretch on the pelvic-urethra reflex potentiation was examined in urethane-anesthetized rats by recording the external urethra sphincter electromyogram activity evoked by the pelvic afferent stimulation. Test stimulation (1 stimulation/30 s) evoked a baseline reflex activity with a single action potential that was abolished by gallamine (5 mg/kg iv). On the other hand, the repetitive stimulation (1 stimulation/1 s) induced spinal reflex potentiation (SRP) that was attenuated by intrathecal 6-cyano-7-nitroquinoxaline- 2,4-dione (a glutamatergic alpha-amino-3-hydroxy-5-methyl- 4-isoxazoleproprionat receptor antagonist, 100 mu M, 10 mu l) and D-2-amino-5-phosphonovalerate [a glutamatergic N-methyl-D-aspartate (NMDA) antagonist, 100 mu M, 10 mu l]. Acute anal stretch using a mosquito clamp with a distance of 4 mm exhibited no effect, whereas distances of 8 mm attenuated and 12 mm abolished the repetitive stimulation-induced SRP. Intrathecal NMDA (100 mu M, 10 mu l) reversed the abolition on SRP caused by anal stretch. On the other hand, pretreated bicuculline [gamma-aminobutyric acid (GABA) A receptor antagonist, 100 mu M, 10 mu l] but not hydroxysaclofen (GABA(B) receptor antagonist) counteracted the abolition on the repetitive stimulation-induced SRP caused by the anal stretch. All of the results suggested that anal stretch may be used as an adjunct to assist voiding dysfunction in patients with overactive urethra sphincter and that GABAergic neurotransmission is important in the neural mechanisms underlying external urethra sphincter activity inhibited by anal stretch

H-Ras oncogene counteracts the growth-inhibitory effect of genistein in T24 bladder carcinoma cells

Among eight human bladder cancer cell lines we examined, only T24 cells were resistant to the growth inhibition effect of genistein, an isoflavone and potent anticancer drug. Since the T24 cell line was the only cell line known to overexpress oncogenic H-Ras(val12), we investigated the role of H-Ras(val 12) in mediating drug resistance. Herein, we demonstrate that the phenotype of T24 cells could be dramatically reversed and became relatively susceptible to growth inhibition by genistein if the synthesis of H- Ras(val 12) or its downstream effector c-Fos had been suppressed. The inhibition of Ras-mediated signalling with protein kinase inhibitors, such as PD58059 and U0126 which inhibited MEK and ERK, in T24 cells also rendered the identical phenotypic reversion. However, this reversion was not observed when an inhibitor was used to suppress the protein phosphorylation function of PI3 K or PKC. These results suggest that the signal mediated by H-Ras(val 12) is predominantly responsible for the resistance of the cells to the anticancer drug genistein