80 research outputs found
Particle-Based Simulations of Electrophoretic Deposition with Adaptive Physics Models
This work represents an extension of mesoscale particle-based modeling of
electrophoretic deposition (EPD), which has relied exclusively on pairwise
interparticle interactions described by Derjaguin-Landau-Verwey-Overbeek (DLVO)
theory. With this standard treatment, particles continuously move and interact
via excluded volume and electrostatic pair potentials under the influence of
external fields throughout the EPD process. The physics imposed by DLVO theory
may not be appropriate to describe all systems, considering the vast material,
operational, and application space available to EPD. As such, we present three
modifications to standard particle-based models, each rooted in the ability to
dynamically change interparticle interactions as simulated deposition
progresses. This approach allows simulations to capture charge transfer and/or
irreversible adsorption based on tunable parameters. We evaluate and compare
simulated deposits formed under new physical assumptions, demonstrating the
range of systems that these adaptive physics models may capture.Comment: 34 pages, 10 figure
Dual inhibition of AKTâmTOR and AR signaling by targeting HDAC3 in PTENâ or SPOPâmutated prostate cancer
Abstract AKTâmTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysineâ63âchain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1. Conditional homozygous deletion of Hdac3 suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in the Pten knockout mouse model. Pharmacological inhibition of HDAC3 using a selective HDAC3 inhibitor RGFP966 inhibits growth of both PTENâdeficient and SPOPâmutated prostate cancer cells in culture, patientâderived organoids and xenografts in mice. Our study identifies HDAC3 as a common upstream activator of AKT and AR signaling and reveals that dual inhibition of AKT and AR pathways is achievable by singleâagent targeting of HDAC3 in prostate cancer
Novel Molecular Targets of Azadirachta indica Associated with Inhibition of Tumor Growth in Prostate Cancer
Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients. Azadirachta indica (common name: neem) contains multiple active compounds that have potent anti-inflammatory and anticancer properties. The present study investigates the novel targets of the anticancer activity of ethanol extract of neem leaves (EENL) in vitro and evaluates the in vivo efficacy in the prostate cancer models. Analysis of the components in the EENL by mass spectrometry suggests the presence of 2â˛,3â˛-dehydrosalannol, 6-desacetyl nimbinene, and nimolinone. Treatment of C4-2B and PC-3M-luc2 prostate cancer cells with EENL inhibited the cell proliferation. Genome-wide expression profiling, using oligonucleotide microarrays, revealed genes differentially expressed with EENL treatment in prostate cancer cells. Functional analysis unveiled that most of the up-regulated genes were associated with cell death, and drug metabolism, and the down-regulated genes were associated with cell cycle, DNA replication, recombination, and repair functions. Quantitative PCR confirmed significant up-regulation of 40 genes and immunoblotting revealed increase in the protein expression levels of HMOX1, AKR1C2, AKR1C3, and AKR1B10. EENL treatment inhibited the growth of C4-2B and PC-3M-luc2 prostate cancer xenografts in nude mice. The suppression of tumor growth is associated with the formation of hyalinized fibrous tumor tissue and the induction of cell death by apoptosis. These results suggest that EENL-containing natural bioactive compounds could have potent anticancer property and the regulation of multiple cellular pathways could exert pleiotrophic effects in prevention and treatment of prostate cancer
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Mechanism and Dynamics of Molecular Exchange at the Silica/Binary Solvent Mixtures Interface.
Nonequilibrium molecular dynamics simulations of acetonitrile/methanol mixtures in contact with a hydroxylated silica surface are used to elucidate the mechanism of molecular exchange at a hydrophilic liquid/solid interface. The different hydrogen-bonding ability of the two solvents provides a driving force for the adsorption/desorption process, which is followed by examining several structural and energetic properties of the system. Two different reaction coordinates for the hydrogen bonding exchange are defined and are used to identify transition states in which the methanol attains a well-defined orientation. The reaction coordinates are used to examine the mechanism and dynamics of the exchange. We find that the exchange process involves multiple recrossing of the transition state and can progress via two different mechanisms, depending whether the methanol first acts as a hydrogen bond donor or acceptor at the silica surface
Mechanism and Dynamics of Molecular Exchange at the Silica/Binary Solvent Mixtures Interface
Nonequilibrium molecular dynamics
simulations of acetonitrile/methanol
mixtures in contact with a hydroxylated silica surface are used to
elucidate the mechanism of molecular exchange at a hydrophilic liquid/solid
interface. The different hydrogen-bonding ability of the two solvents
provides a driving force for the adsorption/desorption process, which
is followed by examining several structural and energetic properties
of the system. Two different reaction coordinates for the hydrogen
bonding exchange are defined and are used to identify transition states
in which the methanol attains a well-defined orientation. The reaction
coordinates are used to examine the mechanism and dynamics of the
exchange. We find that the exchange process involves multiple recrossing
of the transition state and can progress via two different mechanisms,
depending whether the methanol first acts as a hydrogen bond donor
or acceptor at the silica surface
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