Retrovirus budding may constitute a port of entry for drug carriers

AbstractThis paper investigates the relation between viral infection and cell uptake of liposomes and nanoparticles. A defective virus was used to infect two types of cells: cells allowing virus budding (psi2neo cells) and cells bereft of a virus exit process (NIH 3T3 cells). This study has revealed that cell uptake of pH-sensitive-liposomes is highly dependent on the virus exit process, since it ensued only when virus budding occurred. This preferential uptake of pH-sensitive liposomes by infected cells was not carrier-specific because similar uptake was observed with non-biodegradable fluorescent nanoparticles using confocal microscopy. Also, inhibition of neo gene expression by oligonucleotide pH-sensitive-liposomes was only observed in the cell system (psi2neo) endowed with a virus exit process. Finally, increased membrane fluidity was noted in the infected cells, possibly reflecting membrane perturbation due to virus budding. We suggest that this membrane perturbation may be the key to the uptake of the different colloidal carriers. Infected cells could, thus, constitute a natural target for particulate drug carriers

The signature of 44Ti in Cassiopeia A revealed by IBIS/ISGRI on INTEGRAL

We report the detection of both the 67.9 and 78.4 keV 44Sc gamma-ray lines in Cassiopeia A with the INTEGRAL IBIS/ISGRI instrument. Besides the robustness provided by spectro-imaging observations, the main improvements compared to previous measurements are a clear separation of the two 44Sc lines together with an improved significance of the detection of the hard X-ray continuum up to 100 keV. These allow us to refine the determination of the 44Ti yield and to constrain the nature of the nonthermal continuum emission. By combining COMPTEL, BeppoSAX/PDS and ISGRI measurements, we find a line flux of (2.5 +/- 0.3)*10(-5) cm(-2) s(-1) leading to a synthesized 44Ti mass of 1.6 (+0.6-0.3)*10(-4) solar mass. This high value suggests that Cas A is peculiar in comparison to other young supernova remnants, from which so far no line emission from 44Ti decay has been unambiguously detected.Comment: 5 pages, 4 figures, Accepted for publication in ApJ

Efficient Emptiness Check for Timed B\"uchi Automata (Extended version)

The B\"uchi non-emptiness problem for timed automata refers to deciding if a given automaton has an infinite non-Zeno run satisfying the B\"uchi accepting condition. The standard solution to this problem involves adding an auxiliary clock to take care of the non-Zenoness. In this paper, it is shown that this simple transformation may sometimes result in an exponential blowup. A construction avoiding this blowup is proposed. It is also shown that in many cases, non-Zenoness can be ascertained without extra construction. An on-the-fly algorithm for the non-emptiness problem, using non-Zenoness construction only when required, is proposed. Experiments carried out with a prototype implementation of the algorithm are reported.Comment: Published in the Special Issue on Computer Aided Verification - CAV 2010; Formal Methods in System Design, 201

Decoration of squalenoyl-gemcitabine nanoparticles with squalenyl-hydroxybisphosphonate for the treatment of bone tumors

Therapeutic perspectives of bone tumors such as osteosarcom are main restricted due to the inefficacy of current treatments. We propose here the construction of a novel anticancers qualene-based nanomedicine with bone affinity and retention capacity. A squalenyl-hydroxybisphosphonate molecule was synthetized by chemical conjugation of a 1-hydroxyl-1,1-bi-sphosphonatemoiety to the squalenechain. This amphiphilic compound was inserted onto squalenoyl-gemcitabinenano-particles using the nanoprecipitation method. The co-assemblyled to nanoconstructsof 75 nm, with different morphology and colloidal properties. The presence of squalenyl-hydroxybi-sphosphonate enhanced the nanoparticles binding affinity for hydroxyapatite,a mineral present in the bone. Moreover, the in vitro anticancer activity was preserved when tested in commercial and patient-treated derived pedia tricoste osarcomacells. Furtherin vivo studies will shed lighton the potential of these nano medicines for the treatment of bones arcomas

Dual controlled delivery of squalenoyl-gemcitabine and paclitaxel using thermo-responsive polymeric micelles for pancreatic cancer

In this study we report the synthesis of a themroresponsive block copolymer by reversible addition fragmentation transfer polymerization comprising poly(2-ethylhexyl methacrylate)-b-poly[di(ethylene glycol)methyl ether methacrylate-co-oligo(ethylene glycol)methyl ether methacrylate] as hydrophobic and thermoresponsive blocks respectively. The polymer self-assembles into sub-50 micelles and can carry simultaneously two drug molecules, namely squalene-gemcitabine and paclitaxel. Both drugs can be released from the micellar compartment in a thermally controlled manner owing to the controllable disruption of the micellar corona above the lower critical solution temperature of the polymer. We demonstrate that the formulation augments synergistically the cytotoxicity of the two drugs in vitro against a model pancreatic cancer cell line. More importantly, it is shown that the polymer exerts a direct interaction with the cell membrane which further augments the cytotoxicity of the drug cargo in a thermally controlled manne

Insights into the Influence of Priors in Posterior Mapping of Discrete Morphological Characters: A Case Study in Annonaceae

Background - Posterior mapping is an increasingly popular hierarchical Bayesian based method used to infer character histories and reconstruct ancestral states at nodes of molecular phylogenies, notably of morphological characters. As for all Bayesian analyses specification of prior values is an integrative and important part of the analysis. He we provide an example of how alternative prior choices can seriously influence results and mislead interpretations. Methods/Principal Findings - For two contrasting discrete morphological characters, namely a slow and a fast evolving character found in the plant family Annonaceae, we specified a total of eight different prior distributions per character. We investigated how these prior settings affected important summary statistics. Our analyses showed that the different prior distributions had marked effects on the results in terms of average number of character state changes. These differences arise because priors play a crucial role in determining which areas of parameter space the values of the simulation will be drawn from, independent of the data at hand. However, priors seemed to fit the data better if they would result in a more even sampling of parameter space (normal posterior distribution), in which case alternative standard deviation values had little effect on the results. The most probable character history for each character was affected differently by the prior. For the slower evolving character, the same character history always had the highest posterior probability independent of the priors used. In contrast, the faster evolving character showed different most probable character histories depending on the prior. These differences could be related to the level of homoplasy exhibited by each character. Conclusions - Although our analyses were restricted to two morphological characters within a single family, our results underline the importance of carefully choosing prior values for posterior mapping. Prior specification will be of crucial importance when interpreting the results in a meaningful way. It is hard to suggest a statistically sound method for prior specification without more detailed studies. Meanwhile, we propose that the data could be used to estimate the prior value of the gamma distribution placed on the transformation rate in posterior mappin

To adapt or go extinct? The fate of megafaunal palm fruits under past global change

Past global change may have forced animal-dispersed plants with megafaunal fruits to adapt or go extinct, but these processes have remained unexplored at broad spatio-temporal scales. Here, we combine phylogenetic, distributional and fruit size data for more than 2500 palm (Arecaceae) species in a time-slice diversification analysis to quantify how extinction and adaptation have changed over deep time. Our results indicate that extinction rates of palms with megafaunal fruits have increased in the New World since the onset of the Quaternary (2.6 million years ago). In contrast, Old World palms show a Quaternary increase in transition rates towards evolving small fruits from megafaunal fruits. We suggest that Quaternary climate oscillations and concurrent habitat fragmentation and defaunation of megafaunal frugivores in the New World have reduced seed dispersal distances and geographical ranges of palms with megafaunal fruits, resulting in their extinction. The increasing adaptation to smaller fruits in the Old World could reflect selection for seed dispersal by ocean-crossing frugivores (e.g. medium-sized birds and bats) to colonize Indo-Pacific islands against a background of Quaternary sea-level fluctuations. Our macro-evolutionary results suggest that megafaunal fruits are increasingly being lost from tropical ecosystems, either due to extinctions or by adapting to smaller fruit sizes.</p