627 research outputs found
Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives
20(S)-Sulfonylamidine CPT-derivatives were prepared and tested for cytotoxicity.Several analogs showed superior cytotoxic activity compared to irinotecan.Key structural features related to cytotoxicity were identified by SAR analysis.Compounds 9 and 15c interacted with Topo I-DNA by a different binding mode from CPT.These compounds are new generation CPT-derived antitumor agents.In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure–activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π–π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.CPT (green), 9 (magenta), and 15c (blue) in the binding site of DNA-Topo-I
POINeT: protein interactome with sub-network analysis and hub prioritization
<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions (PPIs) are critical to every aspect of biological processes. Expansion of all PPIs from a set of given queries often results in a complex PPI network lacking spatiotemporal consideration. Moreover, the reliability of available PPI resources, which consist of low- and high-throughput data, for network construction remains a significant challenge. Even though a number of software tools are available to facilitate PPI network analysis, an integrated tool is crucial to alleviate the burden on querying across multiple web servers and software tools.</p> <p>Results</p> <p>We have constructed an integrated web service, POINeT, to simplify the process of PPI searching, analysis, and visualization. POINeT merges PPI and tissue-specific expression data from multiple resources. The tissue-specific PPIs and the numbers of research papers supporting the PPIs can be filtered with user-adjustable threshold values and are dynamically updated in the viewer. The network constructed in POINeT can be readily analyzed with, for example, the built-in centrality calculation module and an integrated network viewer. Nodes in global networks can also be ranked and filtered using various network analysis formulas, i.e., centralities. To prioritize the sub-network, we developed a ranking filtered method (S3) to uncover potential novel mediators in the midbody network. Several examples are provided to illustrate the functionality of POINeT. The network constructed from four schizophrenia risk markers suggests that EXOC4 might be a novel marker for this disease. Finally, a liver-specific PPI network has been filtered with adult and fetal liver expression profiles.</p> <p>Conclusion</p> <p>The functionalities provided by POINeT are highly improved compared to previous version of POINT. POINeT enables the identification and ranking of potential novel genes involved in a sub-network. Combining with tissue-specific gene expression profiles, PPIs specific to selected tissues can be revealed. The straightforward interface of POINeT makes PPI search and analysis just a few clicks away. The modular design permits further functional enhancement without hampering the simplicity. POINeT is available at <url>http://poinet.bioinformatics.tw/</url>.</p
Extracellular interactions and ligand degradation shape the nodal morphogen gradient
t The correct distribution and activity of secreted signaling proteins called morphogens is required for many developmental processes. Nodal morphogens play critical roles in embryonic axis formation in many organisms. Models proposed to generate the Nodal gradient include diffusivity, ligand processing, and a temporal activation window. But how the Nodal morphogen gradient forms in vivo remains unclear. Here, we have measured in vivo for the first time, the binding affinity of Nodal ligands to their major cell surface receptor, Acvr2b, and to the Nodal inhibitor, Lefty, by fluorescence cross-correlation spectroscopy. We examined the diffusion coefficient of Nodal ligands and Lefty inhibitors in live zebrafish embryos by fluorescence correlation spectroscopy. We also investigated the contribution of ligand degradation to the Nodal gradient. We show that ligand clearance via degradation shapes the Nodal gradient and correlates with its signaling range. By computational simulations of gradient formation, we demonstrate that diffusivity, extra-cellular interactions, and selective ligand destruction collectively shape the Nodal morphogen gradient
JUNO Conceptual Design Report
The Jiangmen Underground Neutrino Observatory (JUNO) is proposed to determine
the neutrino mass hierarchy using an underground liquid scintillator detector.
It is located 53 km away from both Yangjiang and Taishan Nuclear Power Plants
in Guangdong, China. The experimental hall, spanning more than 50 meters, is
under a granite mountain of over 700 m overburden. Within six years of running,
the detection of reactor antineutrinos can resolve the neutrino mass hierarchy
at a confidence level of 3-4, and determine neutrino oscillation
parameters , , and to
an accuracy of better than 1%. The JUNO detector can be also used to study
terrestrial and extra-terrestrial neutrinos and new physics beyond the Standard
Model. The central detector contains 20,000 tons liquid scintillator with an
acrylic sphere of 35 m in diameter. 17,000 508-mm diameter PMTs with high
quantum efficiency provide 75% optical coverage. The current choice of
the liquid scintillator is: linear alkyl benzene (LAB) as the solvent, plus PPO
as the scintillation fluor and a wavelength-shifter (Bis-MSB). The number of
detected photoelectrons per MeV is larger than 1,100 and the energy resolution
is expected to be 3% at 1 MeV. The calibration system is designed to deploy
multiple sources to cover the entire energy range of reactor antineutrinos, and
to achieve a full-volume position coverage inside the detector. The veto system
is used for muon detection, muon induced background study and reduction. It
consists of a Water Cherenkov detector and a Top Tracker system. The readout
system, the detector control system and the offline system insure efficient and
stable data acquisition and processing.Comment: 328 pages, 211 figure
New measurement of via neutron capture on hydrogen at Daya Bay
This article reports an improved independent measurement of neutrino mixing
angle at the Daya Bay Reactor Neutrino Experiment. Electron
antineutrinos were identified by inverse -decays with the emitted
neutron captured by hydrogen, yielding a data-set with principally distinct
uncertainties from that with neutrons captured by gadolinium. With the final
two of eight antineutrino detectors installed, this study used 621 days of data
including the previously reported 217-day data set with six detectors. The
dominant statistical uncertainty was reduced by 49%. Intensive studies of the
cosmogenic muon-induced Li and fast neutron backgrounds and the
neutron-capture energy selection efficiency, resulted in a reduction of the
systematic uncertainty by 26%. The deficit in the detected number of
antineutrinos at the far detectors relative to the expected number based on the
near detectors yielded in the
three-neutrino-oscillation framework. The combination of this result with the
gadolinium-capture result is also reported.Comment: 26 pages, 23 figure
Notolutesins A–J, Dolabrane-Type Diterpenoids from the Chinese Liverwort Notoscyphus lutescens
Ten new dolabrane-type diterpenoids, notolutesins A–J (1–10), were isolated from the Chinese liverwort Notoscyphus lutescens, along with four known compounds. The structures of the new compounds were established on the basis of extensive spectroscopic data, and that of 1 was confirmed by single-crystal X-ray crystallography. The absolute configuration of 1 was determined by comparing its experimental and calculated electronic circular dichroism spectra. All of the isolates were evaluated for their cytotoxicity against a small panel of human cancer cell lines, and compound 1 exhibited an IC50 value of 6.2 μM against the PC3 human prostate cancer cell line
A new measurement of antineutrino oscillation with the full detector configuration at Daya Bay
We report a new measurement of electron antineutrino disappearance using the
fully-constructed Daya Bay Reactor Neutrino Experiment. The final two of eight
antineutrino detectors were installed in the summer of 2012. Including the 404
days of data collected from October 2012 to November 2013 resulted in a total
exposure of 6.910 GW-ton-days, a 3.6 times increase over
our previous results. Improvements in energy calibration limited variations
between detectors to 0.2%. Removal of six Am-C radioactive
calibration sources reduced the background by a factor of two for the detectors
in the experimental hall furthest from the reactors. Direct prediction of the
antineutrino signal in the far detectors based on the measurements in the near
detectors explicitly minimized the dependence of the measurement on models of
reactor antineutrino emission. The uncertainties in our estimates of
and were halved as a result of these
improvements. Analysis of the relative antineutrino rates and energy spectra
between detectors gave and eV in the three-neutrino
framework.Comment: Updated to match final published versio
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