1,618 research outputs found
Discovery of MDM2-p53 and MDM4-p53 protein-protein interactions small molecule dual inhibitors
MDM2 and MDM4 are key negative regulators of p53, an important protein involved in several cell processes (e. g. cell cycle and apoptosis). Not surprisingly, the p53 tumor suppressor function is inactivated in tumors over -expressing these two proteins. Therefore, both MDM2 and MDM4 are considered important therapeutic targets for an effective reactivation of the p53 function. Herein, we present our studies on the development of spi-ropyrazoline oxindole small molecules able to inhibit MDM2/4-p53 protein-protein interactions (PPIs). Twenty-seven potential spiropyrazoline oxindole dual inhibitors were prepared based on in silico structural optimization studies of a hit compound with MDM2 and MDM4 proteins. The antiproliferative activity of the target com-pounds was evaluated in cancer cell lines harboring wild-type p53 and overexpressing MDM2 and/or MDM4. The most active compounds in SJSA-1 cells, 2q and 3b, induce cell death via apoptosis and control cell growth by targeting the G0/G1 cell cycle checkpoint in a concentration-dependent manner. The ability of the five most active spiropyrazoline oxindoles in dissociating p53 from MDM2 and MDM4 was analyzed by an immu-noenzymatic assay. Three compounds inhibited MDM2/4-p53 PPIs with IC50 values in the nM range, while one compound inhibited more selectively the MDM2-p53 PPI over the MDM4-p53 PPI. Collectively, these results show: i) 3b may serve as a valuable lead for obtaining selective MDM2-p53 PPI inhibitors and more efficient anti-osteosarcoma agents; ii) 2a, 2q and 3f may serve as valuable leads for obtaining dual MDM2/4 inhibitors and more effective p53 activators
Activity to Breast Cancer Cell Lines of Different Malignancy and Predicted Interaction with Protein Kinase C Isoforms of Royleanones
Plants have been used for centuries to treat several illnesses. The Plectranthus genus has a vast variety of species that has allowed the isolation of cytotoxic compounds with notable activities. The abietane diterpenes 6, 7-dehydroroyleanone (DeRoy, 1), 7α-acetoxy-6ÎČ-hydroxyroyleanone (Roy, 2), and Parvifloron D (ParvD, 3) were obtained from Plectranthus spp. and showed promising biological activities, such as cytotoxicity. The inhibitory effects of the different natural abietanes (1-3) were compared in MFC7, SkBr3, and SUM159 cell lines, as well as SUM159 grown in cancer stem cell-inducing conditions. Based on the royleanonesâ bioactivity, the derivatives RoyBz (4), RoyBzCl (5), RoyPr2 (6), and DihydroxyRoy (7), previously obtained from 2, were selected for further studies. Protein kinases C (PKCs) are involved in several carcinogenic processes. Thus, PKCs are potential targets for cancer therapy. To date, the portfolio of available PKC modulators remains very limited due to the difficulty of designing isozyme-selective PKC modulators. As such, molecular docking was used to evaluate royleanones 1-6 as predicted isozyme-selective PKC binders. Subtle changes in the binding site of each PKC isoform change the predicted interaction profiles of the ligands. Subtle changes in royleanone substitution patterns, such as a double substitution only with non-substituted phenyls, or hydroxybenzoate at position four that flips the binding mode of ParvD (3), can increase the predicted interactions in certain PKC subtype
Oxidonitrergic and antioxidant effects of a low molecular weight peptide fraction from hardened bean (Phaseolus vulgaris) on endothelium
About 3000 tons of beans are not used in human food due to hardening. Several studies on bean-derived bioactive peptides have shown potential to treat some diseases, including those relying on oxidative dysfunctions. We assessed the effects of peptides extracted from hardened bean Phaseolus vulgaris (PV) on reactive oxygen species (ROS) and nitric oxide (NO) production, cytotoxic and cytoprotective effects in endothelial cells, and oxidonitrergic-dependent vasodilating effects. Extract was composed by peptide fraction <3 kDa (PV3) from hardened common bean residue. PV3 sequences were obtained and analyzed with bioinformatics. Human umbilical vein endothelial cells were treated with 10, 20, 30, and 250 ”g/mL PV3. Oxidative stress was provoked by 3% H2O2. Cytotoxicity and cytoprotective effects were evaluated by MTT assay, whereas, ROS and NO were quantified using DHE and DAF-FM fluorescent probes by confocal microscopy. NO- and endothelium-dependent vasodilating effects of PV3 were assessed in isolated aortic rings. We found 35 peptides with an average mass of 1.14 kDa. There were no cell deaths with 10 and 20 Όg/mL PV3. PV3 at 30 Όg/mL increased cell viability, while cytotoxicity was observed only with 250 Όg/mL PV3. PV3 at 10 Όg/mL was able to protect cells from oxidative stress. PV3 also increased NO release without causing cell death. It also reduced relative ROS production induced by H2O2. PV3 vasodilating effects relied on endothelium-dependent NO release. PV3 obtained from low-commercial-value bean displays little cytotoxicity and exerts antioxidant effects, whereas it increases endothelial NO release
Fiber Optical Cable and Connector System (FOCCoS) for PFS/Subaru
FOCCoS, Fiber Optical Cable and Connector System, has the main function of
capturing the direct light from the focal plane of Subaru Telescope using
optical fibers, each one with a microlens in its tip, and conducting this light
through a route containing connectors to a set of four spectrographs. The
optical fiber cable is divided in 3 different segments called Cable A, Cable B
and Cable C. Multi-fibers connectors assure precise connection among all
optical fibers of the segments, providing flexibility for instrument changes.
To assure strong and accurate connection, these sets are arranged inside two
types of assemblies: the Tower Connector, for connection between Cable C and
Cable B; and the Gang Connector, for connection between Cable B and Cable A.
Throughput tests were made to evaluate the efficiency of the connections. A
lifetime test connection is in progress. Cable C is installed inside the PFI,
Prime Focus Instrument, where each fiber tip with a microlens is bonded to the
end of the shaft of a 2-stage piezo-electric rotatory motor positioner; this
assembly allows each fiber to be placed anywhere within its patrol region,
which is 9.5mm diameter.. Each positioner uses a fiber arm to support the
ferrule, the microlens, and the optical fiber. 2400 of these assemblies are
arranged on a motor bench plate in a hexagonal-closed-packed disposition.Comment: 11 pages, 20 figure
Azimuthal asymmetry in the risetime of the surface detector signals of the Pierre Auger Observatory
The azimuthal asymmetry in the risetime of signals in Auger surface detector
stations is a source of information on shower development. The azimuthal
asymmetry is due to a combination of the longitudinal evolution of the shower
and geometrical effects related to the angles of incidence of the particles
into the detectors. The magnitude of the effect depends upon the zenith angle
and state of development of the shower and thus provides a novel observable,
, sensitive to the mass composition of cosmic rays
above eV. By comparing measurements with predictions from
shower simulations, we find for both of our adopted models of hadronic physics
(QGSJETII-04 and EPOS-LHC) an indication that the mean cosmic-ray mass
increases slowly with energy, as has been inferred from other studies. However,
the mass estimates are dependent on the shower model and on the range of
distance from the shower core selected. Thus the method has uncovered further
deficiencies in our understanding of shower modelling that must be resolved
before the mass composition can be inferred from .Comment: Replaced with published version. Added journal reference and DO
Molecular excitation in the Interstellar Medium: recent advances in collisional, radiative and chemical processes
We review the different excitation processes in the interstellar mediumComment: Accepted in Chem. Re
Ultrahigh-energy neutrino follow-up of Gravitational Wave events GW150914 and GW151226 with the Pierre Auger Observatory
On September 14, 2015 the Advanced LIGO detectors observed their first
gravitational-wave (GW) transient GW150914. This was followed by a second GW
event observed on December 26, 2015. Both events were inferred to have arisen
from the merger of black holes in binary systems. Such a system may emit
neutrinos if there are magnetic fields and disk debris remaining from the
formation of the two black holes. With the surface detector array of the Pierre
Auger Observatory we can search for neutrinos with energy above 100 PeV from
point-like sources across the sky with equatorial declination from about -65
deg. to +60 deg., and in particular from a fraction of the 90% confidence-level
(CL) inferred positions in the sky of GW150914 and GW151226. A targeted search
for highly-inclined extensive air showers, produced either by interactions of
downward-going neutrinos of all flavors in the atmosphere or by the decays of
tau leptons originating from tau-neutrino interactions in the Earth's crust
(Earth-skimming neutrinos), yielded no candidates in the Auger data collected
within s around or 1 day after the coordinated universal time (UTC)
of GW150914 and GW151226, as well as in the same search periods relative to the
UTC time of the GW candidate event LVT151012. From the non-observation we
constrain the amount of energy radiated in ultrahigh-energy neutrinos from such
remarkable events.Comment: Published version. Added journal reference and DOI. Added Report
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Calibration of the Logarithmic-Periodic Dipole Antenna (LPDA) Radio Stations at the Pierre Auger Observatory using an Octocopter
An in-situ calibration of a logarithmic periodic dipole antenna with a
frequency coverage of 30 MHz to 80 MHz is performed. Such antennas are part of
a radio station system used for detection of cosmic ray induced air showers at
the Engineering Radio Array of the Pierre Auger Observatory, the so-called
Auger Engineering Radio Array (AERA). The directional and frequency
characteristics of the broadband antenna are investigated using a remotely
piloted aircraft (RPA) carrying a small transmitting antenna. The antenna
sensitivity is described by the vector effective length relating the measured
voltage with the electric-field components perpendicular to the incoming signal
direction. The horizontal and meridional components are determined with an
overall uncertainty of 7.4^{+0.9}_{-0.3} % and 10.3^{+2.8}_{-1.7} %
respectively. The measurement is used to correct a simulated response of the
frequency and directional response of the antenna. In addition, the influence
of the ground conductivity and permittivity on the antenna response is
simulated. Both have a negligible influence given the ground conditions
measured at the detector site. The overall uncertainties of the vector
effective length components result in an uncertainty of 8.8^{+2.1}_{-1.3} % in
the square root of the energy fluence for incoming signal directions with
zenith angles smaller than 60{\deg}.Comment: Published version. Updated online abstract only. Manuscript is
unchanged with respect to v2. 39 pages, 15 figures, 2 table
Multi-resolution anisotropy studies of ultrahigh-energy cosmic rays detected at the Pierre Auger Observatory
We report a multi-resolution search for anisotropies in the arrival
directions of cosmic rays detected at the Pierre Auger Observatory with local
zenith angles up to and energies in excess of 4 EeV ( eV). This search is conducted by measuring the angular power spectrum
and performing a needlet wavelet analysis in two independent energy ranges.
Both analyses are complementary since the angular power spectrum achieves a
better performance in identifying large-scale patterns while the needlet
wavelet analysis, considering the parameters used in this work, presents a
higher efficiency in detecting smaller-scale anisotropies, potentially
providing directional information on any observed anisotropies. No deviation
from isotropy is observed on any angular scale in the energy range between 4
and 8 EeV. Above 8 EeV, an indication for a dipole moment is captured; while no
other deviation from isotropy is observed for moments beyond the dipole one.
The corresponding -values obtained after accounting for searches blindly
performed at several angular scales, are in the case of
the angular power spectrum, and in the case of the needlet
analysis. While these results are consistent with previous reports making use
of the same data set, they provide extensions of the previous works through the
thorough scans of the angular scales.Comment: Published version. Added journal reference and DOI. Added Report
Numbe
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