Down-regulation of Survivin enhances sensitivity to BPR0L075 in human cancer cells via caspase-independent mechanisms

Background: BPR0L075 [6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole] is a novel anti-cancer compound. It inhibits tubulin polymerization and induces mitochondrial-dependent apoptosis in various human cancer cells with different multi-drug resistance (MDR) status. Over-expression of an anti-apoptotic molecule, survivin, causes drug-resistance in various cancers. Survivin inhibits apoptosis by interfering caspase-3 and promotes cell growth by stabilizing microtubule networks. Here, we determined the effects of down-regulation of survivin in BPR0L075 (L075) treatment. Methods: Western blot analysis was used to determine the expression level of survivin in L075-untreated/-treated human oral carcinoma KB and nasopharyngeal carcinoma HONE-1 cancer cells. siRNA was used to down-regulate endogenous survivin. MTT cell viability assay, real-time caspase-3 activity assay and immuno-fluorescence microscopy were used to analyze downstream effects. Results: Survivin expression was up-regulated in both KB and HONE-1 cells in response to L075 treatment. Down-regulation of survivin induced hyper-sensitivity to L075 in KB and re-stored sensitivity to L075 in KB-derived L075-resistant KB-L30 cancer cells. At the molecular level, down-regulation of survivin induced changes in microtubule dynamics in both KB and KB-L30 cells. Surprisingly, down-regulation of survivin did not enhance the activity of caspase-3 in L075 therapy. Instead, down-regulation of survivin induced translocation of the apoptosis-inducing factor (AIF) from cytoplasm to nucleus. Conclusion: Down-regulation of survivin improved drug sensitivity to L075 in both KB and L075-resistant KB-L30 cancer cells, possibly through a tubulin-dependent and caspase-independent mechanism. We suggest that combining BPR0L075 and survivin inhibitor may give better clinical outcome than the use of BPR0L075 monotherapy in future clinical trials

Profit Maximization by Forming Federations of Geo-Distributed MEC Platforms

This paper has been presented at: Seventh International Workshop on Cloud Technologies and Energy Efficiency in Mobile Communication Networks (CLEEN 2019). How cloudy and green will mobile network and services be? 15 April 2019 - Marrakech, MoroccoIn press / En prensaMulti-access edge computing (MEC) as an emerging technology which provides cloud service in the edge of multi-radio access networks aims to reduce the service latency experienced by end devices. When individual MEC systems do not have adequate resource capacity to fulfill service requests, forming MEC federations for resource sharing could provide economic incentive to MEC operators. To this end, we need to maximize social welfare in each federation, which involves efficient federation structure generations, federation profit maximization by resource provisioning configuration, and fair profit distribution among participants. We model the problem as a coalition game with difference from prior work in the assumption of latency and locality constraints and also in the consideration of various service policies/demand preferences. Simulation results show that the proposed approach always increases profits. If local requests are served with local resource with priority, federation improves profits without sacrificing request acceptance rates.This work was partially supported by the Ministry of Science and Technology, Taiwan, under grant numbers 106-2221-E-009-004 and by the H2020 collaborative Europe/Taiwan research project 5G-CORAL (grant number 761586)

A Bayesian measurement error model for two-channel cell-based RNAi data with replicates

RNA interference (RNAi) is an endogenous cellular process in which small double-stranded RNAs lead to the destruction of mRNAs with complementary nucleoside sequence. With the production of RNAi libraries, large-scale RNAi screening in human cells can be conducted to identify unknown genes involved in a biological pathway. One challenge researchers face is how to deal with the multiple testing issue and the related false positive rate (FDR) and false negative rate (FNR). This paper proposes a Bayesian hierarchical measurement error model for the analysis of data from a two-channel RNAi high-throughput experiment with replicates, in which both the activity of a particular biological pathway and cell viability are monitored and the goal is to identify short hair-pin RNAs (shRNAs) that affect the pathway activity without affecting cell activity. Simulation studies demonstrate the flexibility and robustness of the Bayesian method and the benefits of having replicates in the experiment. This method is illustrated through analyzing the data from a RNAi high-throughput screening that searches for cellular factors affecting HCV replication without affecting cell viability; comparisons of the results from this HCV study and some of those reported in the literature are included.Comment: Published in at http://dx.doi.org/10.1214/11-AOAS496 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Asteroid Spin-Rate Study using the Intermediate Palomar Transient Factory

Two dedicated asteroid rotation-period surveys have been carried out using data taken on January 6-9 and February 20-23 of 2014 by the Intermediate Palomar Transient Factory (iPTF) in the $R$~band with $\sim 20$-min cadence. The total survey area covered 174~deg$^2$ in the ecliptic plane. Reliable rotation periods for 1,438 asteroids are obtained from a larger data set of 6,551 mostly main-belt asteroids, each with $\geq 10$~detections. Analysis of 1751, PTF based, reliable rotation periods clearly shows the "spin barrier" at $\sim 2$~hours for "rubble-pile" asteroids. We also found a new large-sized super-fast rotator, 2005 UW163 (Chang et al., 2014), and other five candidates as well. Our spin-rate distributions of asteroids with $3 < D < 15$~km shows number decrease when frequency greater than 5 rev/day, which is consistent to that of the Asteroid Light Curve Database (LCDB, Warner et al., 2009) and the result of (Masiero et al., 2009). We found the discrepancy in the spin-rate distribution between our result and (Pravec et al., 2008, update 2014-04-20) is mainly from asteroids with $\Delta m < 0.2$ mag that might be primarily due to different survey strategies. For asteroids with $D \leq 3$~km, we found a significant number drop at $f = 6$ rev/day. The YORP effect timescale for small-sized asteroid is shorter that makes more elongate objets spun up to reach their spin-rate limit and results in break-up. The K-S test suggests a possible difference in the spin-rate distributions of C- and S-type asteroids. We also find that C-type asteroids have a smaller spin-rate limit than the S-type, which agrees with the general sense that the C-type has lower bulk density than the S-type.Comment: Submitted to ApJ (Jan, 2015). Accepted by ApJ (June, 2015). The whole set of the folded lightcurves will be available on the published articl

Survivin counteracts the therapeutic effect of microtubule de-stabilizers by stabilizing tubulin polymers

<p>Abstract</p> <p>Background</p> <p>Survivin is a dual function protein. It inhibits the apoptosis of cells by inhibiting caspases, and also promotes cell growth by stabilizing microtubules during mitosis. Over-expression of survivin has been demonstrated to induce drug-resistance to various chemo-therapeutic agents such as cisplatin (DNA damaging agent) and paclitaxel (microtubule stabilizer) in cancers. However, survivin-induced resistance to microtubule de-stabilizers such as <it>Vinca </it>alkaloids and Combretastatin A-4 (CA-4)-related compounds were seldom demonstrated in the past. Furthermore, the question remains as to whether survivin plays a dominant role in processing cytokinesis or inhibiting caspases activity in cells treated with anti-mitotic compounds. The purpose of this study is to evaluate the effect of survivin on the resistance and susceptibility of human cancer cells to microtubule de-stabilizer-induced cell death.</p> <p>Results</p> <p>BPR0L075 is a CA-4 analog that induces microtubule de-polymerization and subsequent caspase-dependent apoptosis. To study the relationship between the expression of survivin and the resistance to microtubule de-stabilizers, a KB-derived BPR0L075-resistant cancer cell line, KB-<it>L30</it>, was generated for this study. Here, we found that survivin was over-expressed in the KB-<it>L30 </it>cells. Down-regulation of survivin by siRNA induced hyper-sensitivity to BPR0L075 in KB cells and partially re-stored sensitivity to BPR0L075 in KB-<it>L30 </it>cells. Western blot analysis revealed that down-regulation of survivin induced microtubule de-stabilization in both KB and KB-<it>L30 </it>cells. However, the same treatment did not enhance the down-stream caspase-3/-7 activities in BPR0L075-treated KB cells. Translocation of a caspase-independent apoptosis-related molecule, apoptosis-inducing factor (AIF), from cytoplasm to the nucleus was observed in survivin-targeted KB cells under BPR0L075 treatment.</p> <p>Conclusion</p> <p>In this study, survivin plays an important role in the stability of microtubules, but not with caspases inhibition. Over-expression of survivin counteracts the therapeutic effect of microtubule de-stabilizer BPR0L075 probably by stabilizing tubulin polymers, instead of the inhibition of caspase activity in cancer cells. Besides microtubule-related caspase-dependent cell death, caspase-independent mitotic cell death could be initiated in survivin/BPR0L075 combination treatments. We suggest that combining microtubule de-stabilizers with a survivin inhibitor may attribute to a better clinical outcome than the use of anti-mitotic monotherapy in clinical situations.</p

Risk factors and 180-day mortality of acute kidney disease in critically ill patients: A multi-institutional study

BackgroundCritically ill patients with acute kidney injury (AKI) have a poor prognosis. Recently, the Acute Disease Quality Initiative (ADQI) proposed to define acute kidney disease (AKD) as acute or subacute damage and/or loss of kidney function post AKI. We aimed to identify the risk factors for the occurrence of AKD and to determine the predictive value of AKD for 180-day mortality in critically ill patients.MethodsWe evaluated 11,045 AKI survivors and 5,178 AKD patients without AKI, who were admitted to the intensive care unit between 1 January 2001 and 31 May 2018, from the Chang Gung Research Database in Taiwan. The primary and secondary outcomes were the occurrence of AKD and 180-day mortality.ResultsThe incidence rate of AKD among AKI patients who did not receive dialysis or died within 90 days was 34.4% (3,797 of 11,045 patients). Multivariable logistic regression analysis indicated that AKI severity, underlying early CKD, chronic liver disease, malignancy, and use of emergency hemodialysis were independent risk factors of AKD, while male gender, higher lactate levels, use of ECMO, and admission to surgical ICU were negatively correlated with AKD. 180-day mortality was highest among AKD patients without AKI during hospitalization (4.4%, 227 of 5,178 patients), followed by AKI with AKD (2.3%, 88 of 3,797 patients) and AKI without AKD (1.6%, 115 of 7,133 patients). AKI with AKD had a borderline significantly increased risk of 180-day mortality (aOR 1.34, 95% CI 1.00–1.78; p = 0.047), while patients with AKD but no preceding AKI episodes had the highest risk (aOR 2.25, 95% CI 1.71–2.97; p &lt; 0.001).ConclusionThe occurrence of AKD adds limited additional prognostic information for risk stratification of survivors among critically ill patients with AKI but could predict prognosis in survivors without prior AKI

313 new asteroid rotation periods from Palomar Transient Factory observations

A new asteroid rotation period survey have been carried out by using the Palomar Transient Factory (PTF). Twelve consecutive PTF fields, which covered an area of 87 deg$^2$ in the ecliptic plane, were observed in $R$ band with a cadence of $\sim$20 min during February 15--18, 2013. We detected 2500 known asteroids with a diameter range of 0.5 km $\leq D \leq$ 200 km. Of these, 313 objects had highly reliable rotation periods and exhibited the "spin barrier" at $\sim2$ hours. In contrast to the flat spin rate distribution of the asteroids with 3 km $\leq D \leq$ 15 km shown by Pravec et al. (2008), our results deviated somewhat from a Maxwellian distribution and showed a decrease at the spin rate greater than 5 rev/day. One super-fast-rotator candidate and two possible binary asteroids were also found in this work.Comment: 18 pages, 20 figures and 2 very long table

Capturing Cognitive Fingerprints from Keystroke Dynamics

Conventional authentication systems identify a user only at the entry point. Keystroke dynamics can continuously authenticate users by their typing rhythms without extra devices. This article presents a new feature called cognitive typing rhythm (CTR) to continuously verify the identities of computer users. Two machine techniques, SVM and KRR, have been developed for the system. The best results from experiments conducted with 1,977 users show a false-rejection rate of 0.7 percent and a false-acceptance rate of 5.5 percent. CTR therefore constitutes a cognitive fingerprint for continuous. Its effectiveness has been verified through a large-scale dataset. This article is part of a special issue on security

Recurrent disturbances and the degradation of hard coral communities in Taiwan

Recurrent disturbances can have a critical effect on the structure and function of coral reef communities. In this study, long-term changes were examined in the hard coral community at Wanlitung, in southern Taiwan, between 1985 and 2010. In this 26 year interval, the reef has experienced repeated disturbances that include six typhoons and two coral-bleaching events. The frequency of disturbance has meant that species susceptible to disturbance, such as those in the genus Acropora and Montipora have almost disappeared from the reef. Indeed, almost all hard coral species have declined in abundance, with the result that total hard coral cover in 2010 (17.7%) was less than half what it was in 1985 (47.5%). In addition, macro-algal cover has increased from 11.3% in 2003 to 28.5% in 2010. The frequency of disturbance combined with possible chronic influence of a growing human population mean that a diverse reef assemblage is unlikely to persist on this reef into the future