39 research outputs found
Structural basis of colchicine-site targeting acylhydrazones active against multidrug-resistant acute lymphoblastic leukemia
Tubulin is one of the best validated anti-cancer targets, but most anti-tubulin agents have unfavorable therapeutic indexes. Here, we characterized the tubulin-binding activity, the mechanism of action, and the in vivo anti-leukemia efficacy of three 3,4,5-trimethoxy-N-acylhydrazones. We show that all compounds target the colchicine-binding site of tubulin and that none is a substrate of ABC transporters. The crystal structure of the tubulin-bound N-(1′-naphthyl)-3,4,5-trimethoxybenzohydrazide (12) revealed steric hindrance on the T7 loop movement of β-tubulin, thereby rendering tubulin assembly incompetent. Using dose escalation and short-term repeated dose studies, we further report that this compound class is well tolerated to >100 mg/kg in mice. We finally observed that intraperitoneally administered compound 12 significantly prolonged the overall survival of mice transplanted with both sensitive and multidrug-resistant acute lymphoblastic leukemia (ALL) cells. Taken together, this work describes promising colchicine-site-targeting tubulin inhibitors featuring favorable therapeutic effects against ALL and multidrug-resistant cell2195109CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP305896/2013-0; 301596/2017-414/08247-8; 17/14737-6We thank Ganadería Fernando Díaz for calf brains for tubulin purification. The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery.” J.F.D. is a member of the CIB Intramural Program “Molecular Machines for Better Life” (MACBET).
N.M.C. was supported by a fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 14/08247-8, and 17/14737-6). J.A.Y. received a Productivity fellowship from the Brazilian National Counsel of Technological and Scientific Development (CNPq 305896/2013-0 and 301596/2017-4). This work was supported in part by grants BFU2016-75319-R (AEI/FEDER, UE) (J.F.D.) from Ministerio de Economía y Competitividad. The crystal structure work was supported by grants from the Swiss National Science Foundation (31003A_166608, to M.O.S.) and by the COST action CM1407 (to M.O.S.). Part of the in vivo work was supported by R01CA209829 and R01CA213912, Hyundai Hope On Wheels Scholar Grant, Bear Necessities Pediatric Cancer Foundation, Alex’s Lemonade Stand Foundation, the Four Diamonds Fund of the Pennsylvania State University College of Medicine, and the John Wawrynovic Leukemia Research Scholar Endowment (to S.D.
Informe interdisciplinario Barrio “El Molino”
Consideramos importante y fundamental el trabajo en este territorio para poder diseñar alternativas de intervención ante las problemáticas en torno a la salud. Es decir, no solo intentamos tener información al respecto, sino también brindar aportes significativos a través de distintos métodos de intervención, tanto a los vecinos como a la Unidad Sanitaria ubicada en el barrio, a fin de fortalecer lazos entre la institución y el territorio. La intervención se construye a través de diferentes modalidades, que encuentran su sentido común en la apuesta constante de trabajar en pos del mejoramiento de la calidad de vida de los usuarios, y fundamentalmente buscando garantizar la efectivización de los derechos.
Para realizar este abordaje, comenzamos por la búsqueda de información sobre el barrio. Luego, realizamos dos visitas al territorio, donde además de recorrer la zona, conocimos distintas instituciones y organizaciones que forman parte del barrio El Molino. Entre ellas el centro tradicionalista, la asociación civil Punta Arcoiris y la unidad sanitaria El Molino, con el fin de indagar acerca de las condiciones sociales afectadas por las problemáticas de salud a las que se encuentran expuestos los habitantes del lugar.Trabajo final del Curso de Formación Interprofesional en Salud (FIP) (UNLP)Universidad Nacional de La Plat
All-sky search for periodic gravitational waves in LIGO S4 data
We report on an all-sky search with the LIGO detectors for periodic
gravitational waves in the frequency range 50-1000 Hz and with the frequency's
time derivative in the range -1.0E-8 Hz/s to zero. Data from the fourth LIGO
science run (S4) have been used in this search. Three different semi-coherent
methods of transforming and summing strain power from Short Fourier Transforms
(SFTs) of the calibrated data have been used. The first, known as "StackSlide",
averages normalized power from each SFT. A "weighted Hough" scheme is also
developed and used, and which also allows for a multi-interferometer search.
The third method, known as "PowerFlux", is a variant of the StackSlide method
in which the power is weighted before summing. In both the weighted Hough and
PowerFlux methods, the weights are chosen according to the noise and detector
antenna-pattern to maximize the signal-to-noise ratio. The respective
advantages and disadvantages of these methods are discussed. Observing no
evidence of periodic gravitational radiation, we report upper limits; we
interpret these as limits on this radiation from isolated rotating neutron
stars. The best population-based upper limit with 95% confidence on the
gravitational-wave strain amplitude, found for simulated sources distributed
isotropically across the sky and with isotropically distributed spin-axes, is
4.28E-24 (near 140 Hz). Strict upper limits are also obtained for small patches
on the sky for best-case and worst-case inclinations of the spin axes.Comment: 39 pages, 41 figures An error was found in the computation of the C
parameter defined in equation 44 which led to its overestimate by 2^(1/4).
The correct values for the multi-interferometer, H1 and L1 analyses are 9.2,
9.7, and 9.3, respectively. Figure 32 has been updated accordingly. None of
the upper limits presented in the paper were affecte
Search for gravitational waves from binary inspirals in S3 and S4 LIGO data
We report on a search for gravitational waves from the coalescence of compact
binaries during the third and fourth LIGO science runs. The search focused on
gravitational waves generated during the inspiral phase of the binary
evolution. In our analysis, we considered three categories of compact binary
systems, ordered by mass: (i) primordial black hole binaries with masses in the
range 0.35 M(sun) < m1, m2 < 1.0 M(sun), (ii) binary neutron stars with masses
in the range 1.0 M(sun) < m1, m2 < 3.0 M(sun), and (iii) binary black holes
with masses in the range 3.0 M(sun)< m1, m2 < m_(max) with the additional
constraint m1+ m2 < m_(max), where m_(max) was set to 40.0 M(sun) and 80.0
M(sun) in the third and fourth science runs, respectively. Although the
detectors could probe to distances as far as tens of Mpc, no gravitational-wave
signals were identified in the 1364 hours of data we analyzed. Assuming a
binary population with a Gaussian distribution around 0.75-0.75 M(sun), 1.4-1.4
M(sun), and 5.0-5.0 M(sun), we derived 90%-confidence upper limit rates of 4.9
yr^(-1) L10^(-1) for primordial black hole binaries, 1.2 yr^(-1) L10^(-1) for
binary neutron stars, and 0.5 yr^(-1) L10^(-1) for stellar mass binary black
holes, where L10 is 10^(10) times the blue light luminosity of the Sun.Comment: 12 pages, 11 figure
A Joint Search for Gravitational Wave Bursts with AURIGA and LIGO
The first simultaneous operation of the AURIGA detector and the LIGO
observatory was an opportunity to explore real data, joint analysis methods
between two very different types of gravitational wave detectors: resonant bars
and interferometers. This paper describes a coincident gravitational wave burst
search, where data from the LIGO interferometers are cross-correlated at the
time of AURIGA candidate events to identify coherent transients. The analysis
pipeline is tuned with two thresholds, on the signal-to-noise ratio of AURIGA
candidate events and on the significance of the cross-correlation test in LIGO.
The false alarm rate is estimated by introducing time shifts between data sets
and the network detection efficiency is measured with simulated signals with
power in the narrower AURIGA band. In the absence of a detection, we discuss
how to set an upper limit on the rate of gravitational waves and to interpret
it according to different source models. Due to the short amount of analyzed
data and to the high rate of non-Gaussian transients in the detectors noise at
the time, the relevance of this study is methodological: this was the first
joint search for gravitational wave bursts among detectors with such different
spectral sensitivity and the first opportunity for the resonant and
interferometric communities to unify languages and techniques in the pursuit of
their common goal.Comment: 18 pages, IOP, 12 EPS figure
Search for gravitational-wave bursts in LIGO data from the fourth science run
The fourth science run of the LIGO and GEO 600 gravitational-wave detectors,
carried out in early 2005, collected data with significantly lower noise than
previous science runs. We report on a search for short-duration
gravitational-wave bursts with arbitrary waveform in the 64-1600 Hz frequency
range appearing in all three LIGO interferometers. Signal consistency tests,
data quality cuts, and auxiliary-channel vetoes are applied to reduce the rate
of spurious triggers. No gravitational-wave signals are detected in 15.5 days
of live observation time; we set a frequentist upper limit of 0.15 per day (at
90% confidence level) on the rate of bursts with large enough amplitudes to be
detected reliably. The amplitude sensitivity of the search, characterized using
Monte Carlo simulations, is several times better than that of previous
searches. We also provide rough estimates of the distances at which
representative supernova and binary black hole merger signals could be detected
with 50% efficiency by this analysis.Comment: Corrected amplitude sensitivities (7% change on average); 30 pages,
submitted to Classical and Quantum Gravit
Search for Gravitational Waves Associated with 39 Gamma-Ray Bursts Using Data from the Second, Third, and Fourth LIGO Runs
We present the results of a search for short-duration gravitational-wave
bursts associated with 39 gamma-ray bursts (GRBs) detected by gamma-ray
satellite experiments during LIGO's S2, S3, and S4 science runs. The search
involves calculating the crosscorrelation between two interferometer data
streams surrounding the GRB trigger time. We search for associated
gravitational radiation from single GRBs, and also apply statistical tests to
search for a gravitational-wave signature associated with the whole sample. For
the sample examined, we find no evidence for the association of gravitational
radiation with GRBs, either on a single-GRB basis or on a statistical basis.
Simulating gravitational-wave bursts with sine-gaussian waveforms, we set upper
limits on the root-sum-square of the gravitational-wave strain amplitude of
such waveforms at the times of the GRB triggers. We also demonstrate how a
sample of several GRBs can be used collectively to set constraints on
population models. The small number of GRBs and the significant change in
sensitivity of the detectors over the three runs, however, limits the
usefulness of a population study for the S2, S3, and S4 runs. Finally, we
discuss prospects for the search sensitivity for the ongoing S5 run, and beyond
for the next generation of detectors.Comment: 24 pages, 10 figures, 14 tables; minor changes to text and Fig. 2;
accepted by Phys. Rev.
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
Upper limit map of a background of gravitational waves
We searched for an anisotropic background of gravitational waves using data
from the LIGO S4 science run and a method that is optimized for point sources.
This is appropriate if, for example, the gravitational wave background is
dominated by a small number of distinct astrophysical sources. No signal was
seen. Upper limit maps were produced assuming two different power laws for the
source strain power spectrum. For an f^-3 power law and using the 50 Hz to 1.8
kHz band the upper limits on the source strain power spectrum vary between
1.2e-48 Hz^-1 (100 Hz/f)^3 and 1.2e-47 Hz^-1 (100 Hz /f)^3, depending on the
position in the sky. Similarly, in the case of constant strain power spectrum,
the upper limits vary between 8.5e-49 Hz^-1 and 6.1e-48 Hz^-1.
As a side product a limit on an isotropic background of gravitational waves
was also obtained. All limits are at the 90% confidence level. Finally, as an
application, we focused on the direction of Sco-X1, the closest low-mass X-ray
binary. We compare the upper limit on strain amplitude obtained by this method
to expectations based on the X-ray luminosity of Sco-X1.Comment: 11 pages, 9 figures, 2 table