164 research outputs found
On the global hydration kinetics of tricalcium silicate cement
We reconsider a number of measurements for the overall hydration kinetics of
tricalcium silicate pastes having an initial water to cement weight ratio close
to 0.5. We find that the time dependent ratio of hydrated and unhydrated silica
mole numbers can be well characterized by two power-laws in time, . For early times we find an `accelerated' hydration
() and for later times a `deaccelerated' behavior (). The crossover time is estimated as . We
interpret these results in terms of a global second order rate equation
indicating that (a) hydrates catalyse the hydration process for , (b)
they inhibit further hydration for and (c) the value of the
associated second order rate constant is of magnitude 6x10^{-7} - 7x10^{-6}
liter mol^{-1} s^{-1}. We argue, by considering the hydration process actually
being furnished as a diffusion limited precipitation that the exponents and directly indicate a preferentially `plate' like hydrate
microstructure. This is essentially in agreement with experimental observations
of cellular hydrate microstructures for this class of materials.Comment: RevTeX macros, 6 pages, 4 postscript figure
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Dielectronic satellite spectrum of helium-like iron (Fe XXV)
Dielectronic satellite spectra of Fe XXV near 1.8500 A have been observed from PLT (Princeton Large Torus) tokamak plasma discharges for electron temperatures in the range from 1.5 to 3 keV and an electron density of 2 x 10/sup 13/ cm/sup -3/. The electron temperature was independently determined from the electron cyclotron radiation emitted by the plasma. The quality of the spectra allows a detailed comparison with theoretical prediction, which is of importance in view of diagnostic applications
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Varieties of sawtooth behavior in TFTR plasmas
The side-viewing soft-x-ray camera on the Tokamak Fusion Test Reactor (TFTR) has made possible the observation of several different forms of sawtooth oscillation, which can be categorized according to their position in the plasma, sequence of occurrence, and patterns of associated MHD oscillation. Some insight into the plasma conditions involved can be gained by examining the waveforms in detail, along with electron temperature profiles from electron cyclotron emission measurements
Satellite spectra for helium-like titanium. Part II
K/sup ..cap alpha../ x-ray spectra of helium-like titanium, Ti XXI, from Tokamak Fusion Test Reactor (TFTR) plasmas have been observed with a high resolution crystal spectrometer and have been used as a diagnostic of central plasma parameters. The data allow detailed comparison with recent theoretical predictions for the Ti XXI helium-like lines and the associated satellite spectrum in the wavelength range from 2.6000 to 2.6400 A. Improved values for the excitation rate coefficients of the Ti XXI resonance line, the intercombination lines and the forbidden line, and new theoretical results on the wavelengths and transition probabilities for beryllium-like satellites due to transitions of the type 1s/sup 2/ 2lnl' - 1s2p2l'' nl'' with n = 2-4 have been calculated
Replication and Virus-Induced Transcriptome of HAdV-5 in Normal Host Cells versus Cancer Cells - Differences of Relevance for Adenoviral Oncolysis
Adenoviruses (Ads), especially HAdV-5, have been genetically equipped with tumor-restricted replication potential to enable applications in oncolytic cancer therapy. Such oncolytic adenoviruses have been well tolerated in cancer patients, but their anti-tumor efficacy needs to be enhanced. In this regard, it should be considered that cancer cells, dependent on their tissue of origin, can differ substantially from the normal host cells to which Ads are adapted by complex virus-host interactions. Consequently, viral replication efficiency, a key determinant of oncolytic activity, might be suboptimal in cancer cells. Therefore, we have analyzed both the replication kinetics of HAdV-5 and the virus-induced transcriptome in human bronchial epithelial cells (HBEC) in comparison to cancer cells. This is the first report on genome-wide expression profiling of Ads in their native host cells. We found that E1A expression and onset of viral genome replication are most rapid in HBEC and considerably delayed in melanoma cells. In squamous cell lung carcinoma cells, we observed intermediate HAdV-5 replication kinetics. Infectious particle production, viral spread and lytic activity of HAdV-5 were attenuated in melanoma cells versus HBEC. Expression profiling at the onset of viral genome replication revealed that HAdV-5 induced the strongest changes in the cellular transcriptome in HBEC, followed by lung cancer and melanoma cells. We identified prominent regulation of genes involved in cell cycle and DNA metabolism, replication and packaging in HBEC, which is in accord with the necessity to induce S phase for viral replication. Strikingly, in melanoma cells HAdV-5 triggered opposing regulation of said genes and, in contrast to lung cancer cells, no weak S phase induction was detected when using the E2F promoter as reporter. Our results provide a rationale for improving oncolytic adenoviruses either by adaptation of viral infection to target tumor cells or by modulating tumor cell functions to better support viral replication
Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer
Background Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fallen short of their expected therapeutic value as monotherapies. Consequently, new approaches to generating highly potent oncolytic viruses are needed. To address this need, we developed a new method that we term “Directed Evolution” for creating highly potent oncolytic viruses. Methodology/Principal Findings Taking the “Directed Evolution” approach, viral diversity was increased by pooling an array of serotypes, then passaging the pools under conditions that invite recombination between serotypes. These highly diverse viral pools were then placed under stringent directed selection to generate and identify highly potent agents. ColoAd1, a complex Ad3/Ad11p chimeric virus, was the initial oncolytic virus derived by this novel methodology. ColoAd1, the first described non-Ad5-based oncolytic Ad, is 2–3 logs more potent and selective than the parent serotypes or the most clinically advanced oncolytic Ad, ONYX-015, in vitro. ColoAd1's efficacy was further tested in vivo in a colon cancer liver metastasis xenograft model following intravenous injection and its ex vivo selectivity was demonstrated on surgically-derived human colorectal tumor tissues. Lastly, we demonstrated the ability to arm ColoAd1 with an exogenous gene establishing the potential to impact the treatment of cancer on multiple levels from a single agent. Conclusions/Significance Using the “Directed Evolution” methodology, we have generated ColoAd1, a novel chimeric oncolytic virus. In vitro, this virus demonstrated a >2 log increase in both potency and selectivity when compared to ONYX-015 on colon cancer cells. These results were further supported by in vivo and ex vivo studies. Furthermore, these results have validated this methodology as a new general approach for deriving clinically-relevant, highly potent anti-cancer virotherapies
Directed adenovirus evolution using engineered mutator viral polymerases
Adenoviruses (Ads) are the most frequently used viruses for oncolytic and gene therapy purposes. Most Ad-based vectors have been generated through rational design. Although this led to significant vector improvements, it is often hampered by an insufficient understanding of Ad’s intricate functions and interactions. Here, to evade this issue, we adopted a novel, mutator Ad polymerase-based, ‘accelerated-evolution’ approach that can serve as general method to generate or optimize adenoviral vectors. First, we site specifically substituted Ad polymerase residues located in either the nucleotide binding pocket or the exonuclease domain. This yielded several polymerase mutants that, while fully supportive of viral replication, increased Ad’s intrinsic mutation rate. Mutator activities of these mutants were revealed by performing deep sequencing on pools of replicated viruses. The strongest identified mutators carried replacements of residues implicated in ssDNA binding at the exonuclease active site. Next, we exploited these mutators to generate the genetic diversity required for directed Ad evolution. Using this new forward genetics approach, we isolated viral mutants with improved cytolytic activity. These mutants revealed a common mutation in a splice acceptor site preceding the gene for the adenovirus death protein (ADP). Accordingly, the isolated viruses showed high and untimely expression of ADP, correlating with a severe deregulation of E3 transcript splicing
Fiber Mediated Receptor Masking in Non-Infected Bystander Cells Restricts Adenovirus Cell Killing Effect but Promotes Adenovirus Host Co-Existence
The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses
Current profile modification during lower hybrid current drive in the Princeton Beta Experiment-Modification
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