ZNF93 Increases Resistance to ET-743 (Trabectedin; Yondelis®) and PM00104 (Zalypsis®) in Human Cancer Cell Lines

ET-743 (trabectedin, Yondelis) and PM00104 (Zalypsis) are marine derived compounds that have antitumor activity. ET-743 and PM00104 exposure over sustained periods of treatment will result in the development of drug resistance, but the mechanisms which lead to resistance are not yet understood.Human chondrosarcoma cell lines resistant to ET-743 (CS-1/ER) or PM00104 (CS-1/PR) were established in this study. The CS-1/ER and CS-1/PR exhibited cross resistance to cisplatin and methotrexate but not to doxorubicin. Human Affymetrix Gene Chip arrays were used to examine relative gene expression in these cell lines. We found that a large number of genes have altered expression levels in CS-1/ER and CS-1/PR when compared to the parental cell line. 595 CS-1/ER and 498 CS-1/PR genes were identified as overexpressing; 856 CS-1/ER and 874 CS-1/PR transcripts were identified as underexpressing. Three zinc finger protein (ZNF) genes were on the top 10 overexpressed genes list. These genes have not been previously associated with drug resistance in tumor cells. Differential expressions of ZNF93 and ZNF43 genes were confirmed in both CS-1/ER and CS-1/PR resistant cell lines by real-time RT-PCR. ZNF93 was overexpressed in two ET-743 resistant Ewing sarcoma cell lines as well as in a cisplatin resistant ovarian cancer cell line, but was not overexpressed in paclitaxel resistant cell lines. ZNF93 knockdown by siRNA in CS-1/ER and CS-1/PR caused increased sensitivity for ET-743, PM00104, and cisplatin. Furthermore, ZNF93 transfected CS-1 cells are relatively resistant to ET-743, PM00104 and cisplatin.This study suggests that zinc finger proteins, and ZNF93 in particular, are involved in resistance to ET-743 and PM00104

Upper Limits on a Stochastic Gravitational-wave Background Using LIGO and Virgo Interferometers at 600-1000 Hz

A stochastic background of gravitational waves is expected to arise from a superposition of many incoherent sources of gravitational waves, of either cosmological or astrophysical origin. This background is a target for the current generation of ground-based detectors. In this article we present the first joint search for a stochastic background using data from the LIGO and Virgo interferometers. In a frequency band of 600-1000 Hz, we obtained a 95% upper limit on the amplitude of ΩGW(f) ≥Ω3(f/900Hz)3, of Ω

Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Implications For The Origin Of GRB 051103 From LIGO Observations

We present the results of a LIGO search for gravitational waves (GWs) associated with GRB 051103, a short-duration hard-spectrum gamma-ray burst (GRB) whose electromagnetically determined sky position is coincident with the spiral galaxy M81, which is 3.6 Mpc from Earth. Possible progenitors for short-hard GRBs include compact object mergers and soft gamma repeater (SGR) giant flares. A merger progenitor would produce a characteristic GW signal that should be detectable at the distance of M81, while GW emission from an SGR is not expected to be detectable at that distance. We found no evidence of a GW signal associated with GRB 051103. Assuming weakly beamed gamma-ray emission with a jet semi-angle of 30 deg we exclude a binary neutron star merger in M81 as the progenitor with a confidence of 98%. Neutron star-black hole mergers are excluded with > 99% confidence. If the event occurred in M81 our findings support the the hypothesis that GRB 051103 was due to an SGR giant flare, making it the most distant extragalactic magnetar observed to date.Comment: 8 pages, 3 figures. For a repository of data used in the publication, go to: https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=15166 . Also see the announcement for this paper on ligo.org at: http://www.ligo.org/science/Publication-GRB051103/index.ph

Search for Gravitational Waves from Low Mass Compact Binary Coalescence in LIGO's Sixth Science Run and Virgo's Science Runs 2 and 3

We report on a search for gravitational waves from coalescing compact binaries using LIGO and Virgo observations between July 7, 2009 and October 20, 2010. We searched for signals from binaries with total mass between 2 and 25 solar masses; this includes binary neutron stars, binary black holes, and binaries consisting of a black hole and neutron star. The detectors were sensitive to systems up to 40 Mpc distant for binary neutron stars, and further for higher mass systems. No gravitational-wave signals were detected. We report upper limits on the rate of compact binary coalescence as a function of total mass, including the results from previous LIGO and Virgo observations. The cumulative 90%-confidence rate upper limits of the binary coalescence of binary neutron star, neutron star- black hole and binary black hole systems are 1.3 x 10^{-4}, 3.1 x 10^{-5} and 6.4 x 10^{-6} Mpc^{-3}yr^{-1}, respectively. These upper limits are up to a factor 1.4 lower than previously derived limits. We also report on results from a blind injection challenge.Comment: 11 pages, 5 figures. For a repository of data used in the publication, go to: . Also see the announcement for this paper on ligo.org at: <http://www.ligo.org/science/Publication-S6CBCLowMass/index.php

Swift follow-up observations of candidate gravitational-wave transient events

We present the first multi-wavelength follow-up observations of two candidate gravitational-wave (GW) transient events recorded by LIGO and Virgo in their 2009-2010 science run. The events were selected with low latency by the network of GW detectors and their candidate sky locations were observed by the Swift observatory. Image transient detection was used to analyze the collected electromagnetic data, which were found to be consistent with background. Off-line analysis of the GW data alone has also established that the selected GW events show no evidence of an astrophysical origin; one of them is consistent with background and the other one was a test, part of a "blind injection challenge". With this work we demonstrate the feasibility of rapid follow-ups of GW transients and establish the sensitivity improvement joint electromagnetic and GW observations could bring. This is a first step toward an electromagnetic follow-up program in the regime of routine detections with the advanced GW instruments expected within this decade. In that regime multi-wavelength observations will play a significant role in completing the astrophysical identification of GW sources. We present the methods and results from this first combined analysis and discuss its implications in terms of sensitivity for the present and future instruments.Comment: Submitted for publication 2012 May 25, accepted 2012 October 25, published 2012 November 21, in ApJS, 203, 28 ( http://stacks.iop.org/0067-0049/203/28 ); 14 pages, 3 figures, 6 tables; LIGO-P1100038; Science summary at http://www.ligo.org/science/Publication-S6LVSwift/index.php ; Public access area to figures, tables at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p110003

A First Search for coincident Gravitational Waves and High Energy Neutrinos using LIGO, Virgo and ANTARES data from 2007

We present the results of the first search for gravitational wave bursts associated with high energy neutrinos. Together, these messengers could reveal new, hidden sources that are not observed by conventional photon astronomy, particularly at high energy. Our search uses neutrinos detected by the underwater neutrino telescope ANTARES in its 5 line configuration during the period January - September 2007, which coincided with the fifth and first science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed for candidate gravitational-wave signals coincident in time and direction with the neutrino events. No significant coincident events were observed. We place limits on the density of joint high energy neutrino - gravitational wave emission events in the local universe, and compare them with densities of merger and core-collapse events.Comment: 19 pages, 8 figures, science summary page at http://www.ligo.org/science/Publication-S5LV_ANTARES/index.php. Public access area to figures, tables at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p120000

Implementation and testing of the first prompt search for gravitational wave transients with electromagnetic counterparts

Aims. A transient astrophysical event observed in both gravitational wave (GW) and electromagnetic (EM) channels would yield rich scientific rewards. A first program initiating EM follow-ups to possible transient GW events has been developed and exercised by the LIGO and Virgo community in association with several partners. In this paper, we describe and evaluate the methods used to promptly identify and localize GW event candidates and to request images of targeted sky locations. Methods. During two observing periods (Dec 17 2009 to Jan 8 2010 and Sep 2 to Oct 20 2010), a low-latency analysis pipeline was used to identify GW event candidates and to reconstruct maps of possible sky locations. A catalog of nearby galaxies and Milky Way globular clusters was used to select the most promising sky positions to be imaged, and this directional information was delivered to EM observatories with time lags of about thirty minutes. A Monte Carlo simulation has been used to evaluate the low-latency GW pipeline's ability to reconstruct source positions correctly. Results. For signals near the detection threshold, our low-latency algorithms often localized simulated GW burst signals to tens of square degrees, while neutron star/neutron star inspirals and neutron star/black hole inspirals were localized to a few hundred square degrees. Localization precision improves for moderately stronger signals. The correct sky location of signals well above threshold and originating from nearby galaxies may be observed with ~50% or better probability with a few pointings of wide-field telescopes.Comment: 17 pages. This version (v2) includes two tables and 1 section not included in v1. Accepted for publication in Astronomy & Astrophysic