A novel therapeutic strategy for pancreatic neoplasia using a novel RNAi platform targeting PDX-1

Bi-functional shRNA (bi-shRNA), a novel RNA interference (RNAi) effector platform targeting PDX-1 utilizing a systemic DOTAP-Cholesterol delivery vehicle, was studied in three mouse models of progressive pancreatic neoplasia. Species-specific bi-functional PDX-1 shRNA (bi-shRNAPDX-1) lipoplexes inhibited insulin expression and secretion while also substantially inhibiting proliferation of mouse and human cell lines via disruption of cell cycle proteins in vitro. Three cycles of either bi-shRNA<sup>mousePDX-1</sup> or shRNA<sup>mousePDX-1</sup> lipoplexes administered intravenously prevented death from hyperinsulinemia and hypoglycemia in a lethal insulinoma mouse model. Three cycles of shRNA<sup>mousePDX-1</sup> lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of pancreatic neoplasia. Moreover, three cycles of the bi-shRNA<sup>humanPDX-1</sup> lipoplexes resulted in near complete ablation of tumor volume and considerably improved survival in a human PANC-1 implanted SCID-mouse model. Human pancreatic neoplasia specimens also stained strongly for PDX-1 expression. Together, these data support the clinical development of a novel therapeutic strategy using systemic bi-shRNA<sup>PDX-1</sup> lipoplexes against pancreatic neoplasia

Turnip mosaic potyvirus probably first spread to Eurasian brassica crops from wild orchids about 1000 years ago

Turnip mosaic potyvirus (TuMV) is probably the most widespread and damaging virus that infects cultivated brassicas worldwide. Previous work has indicated that the virus originated in western Eurasia, with all of its closest relatives being viruses of monocotyledonous plants. Here we report that we have identified a sister lineage of TuMV-like potyviruses (TuMV-OM) from European orchids. The isolates of TuMV-OM form a monophyletic sister lineage to the brassica-infecting TuMVs (TuMV-BIs), and are nested within a clade of monocotyledon-infecting viruses. Extensive host-range tests showed that all of the TuMV-OMs are biologically similar to, but distinct from, TuMV-BIs and do not readily infect brassicas. We conclude that it is more likely that TuMV evolved from a TuMV-OM-like ancestor than the reverse. We did Bayesian coalescent analyses using a combination of novel and published sequence data from four TuMV genes [helper component-proteinase protein (HC-Pro), protein 3(P3), nuclear inclusion b protein (NIb), and coat protein (CP)]. Three genes (HC-Pro, P3, and NIb), but not the CP gene, gave results indicating that the TuMV-BI viruses diverged from TuMV-OMs around 1000 years ago. Only 150 years later, the four lineages of the present global population of TuMV-BIs diverged from one another. These dates are congruent with historical records of the spread of agriculture in Western Europe. From about 1200 years ago, there was a warming of the climate, and agriculture and the human population of the region greatly increased. Farming replaced woodlands, fostering viruses and aphid vectors that could invade the crops, which included several brassica cultivars and weeds. Later, starting 500 years ago, inter-continental maritime trade probably spread the TuMV-BIs to the remainder of the world

Ab initio theory of helix-coil phase transition

In this paper we suggest a theoretical method based on the statistical mechanics for treating the alpha-helix-random coil transition in alanine polypeptides. We consider this process as a first-order phase transition and develop a theory which is free of model parameters and is based solely on fundamental physical principles. It describes essential thermodynamical properties of the system such as heat capacity, the phase transition temperature and others from the analysis of the polypeptide potential energy surface calculated as a function of two dihedral angles, responsible for the polypeptide twisting. The suggested theory is general and with some modification can be applied for the description of phase transitions in other complex molecular systems (e.g. proteins, DNA, nanotubes, atomic clusters, fullerenes).Comment: 24 pages, 3 figure

The U(1) Gross-Neveu Model at Non-Zero Chemical Potential

The four-fermi model with continuous chiral symmetry is studied in three dimensions at non-zero chemical potential $\mu$ using both the $1/N_f$ expansion and computer simulations. For strong coupling this model spontaneously breaks its U(1) chiral symmetry at zero chemical potential and the Goldstone mechanism is realized through massless pions. The computer simulation predicts a critical chemical potential $\mu_c$ close to the lightest fermion mass in the model. As $\mu$ is increased beyond $\mu_c$, the pion screening mass increases rapidly from zero to a nonvanishing value indicating symmetry restoration. Some lessons are drawn relevant to lattice QCD simulations at non-zero $\mu$.Comment: 26 pages of RevTeX, + 24 figure

The Chandra Source Catalog

The Chandra Source Catalog (CSC) is a general purpose virtual X-ray astrophysics facility that provides access to a carefully selected set of generally useful quantities for individual X-ray sources, and is designed to satisfy the needs of a broad-based group of scientists, including those who may be less familiar with astronomical data analysis in the X-ray regime. The first release of the CSC includes information about 94,676 distinct X-ray sources detected in a subset of public ACIS imaging observations from roughly the first eight years of the Chandra mission. This release of the catalog includes point and compact sources with observed spatial extents <~ 30''. The catalog (1) provides access to the best estimates of the X-ray source properties for detected sources, with good scientific fidelity, and directly supports scientific analysis using the individual source data; (2) facilitates analysis of a wide range of statistical properties for classes of X-ray sources; and (3) provides efficient access to calibrated observational data and ancillary data products for individual X-ray sources, so that users can perform detailed further analysis using existing tools. The catalog includes real X-ray sources detected with flux estimates that are at least 3 times their estimated 1 sigma uncertainties in at least one energy band, while maintaining the number of spurious sources at a level of <~ 1 false source per field for a 100 ks observation. For each detected source, the CSC provides commonly tabulated quantities, including source position, extent, multi-band fluxes, hardness ratios, and variability statistics, derived from the observations in which the source is detected. In addition to these traditional catalog elements, for each X-ray source the CSC includes an extensive set of file-based data products that can be manipulated interactively.Comment: To appear in The Astrophysical Journal Supplement Series, 53 pages, 27 figure

Lung Cancer Risk after Exposure to Polycyclic Aromatic Hydrocarbons: A Review and Meta-Analysis

Typical polycyclic aromatic hydrocarbon mixtures are established lung carcinogens, but the quantitative exposure–response relationship is less clear. To clarify this relationship we conducted a review and meta-analysis of published reports of occupational epidemiologic studies. Thirty-nine cohorts were included. The average estimated unit relative risk (URR) at 100 μg/m(3) years benzo[a]pyrene was 1.20 [95% confidence interval (CI), 1.11–1.29] and was not sensitive to particular studies or analytic methods. However, the URR varied by industry. The estimated means in coke ovens, gasworks, and aluminum production works were similar (1.15–1.17). Average URRs in other industries were higher but imprecisely estimated, with those for asphalt (17.5; CI, 4.21–72.78) and chimney sweeps (16.2; CI, 1.64–160.7) significantly higher than the three above. There was no statistically significant variation of URRs within industry or in relation to study design (including whether adjusted for smoking), or source of exposure information. Limited information on total dust exposure did not suggest that dust exposure was an important confounder or modified the effect. These results provide a more secure basis for risk assessment than was previously available

Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics

Background: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. Methodology/Principal Findings: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. Conclusions/Significance: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy

Statistical Characterization of the Chandra Source Catalog

The first release of the Chandra Source Catalog (CSC) contains ~95,000 X-ray sources in a total area of ~0.75% of the entire sky, using data from ~3,900 separate ACIS observations of a multitude of different types of X-ray sources. In order to maximize the scientific benefit of such a large, heterogeneous data-set, careful characterization of the statistical properties of the catalog, i.e., completeness, sensitivity, false source rate, and accuracy of source properties, is required. Characterization efforts of other, large Chandra catalogs, such as the ChaMP Point Source Catalog (Kim et al. 2007) or the 2 Mega-second Deep Field Surveys (Alexander et al. 2003), while informative, cannot serve this purpose, since the CSC analysis procedures are significantly different and the range of allowable data is much less restrictive. We describe here the characterization process for the CSC. This process includes both a comparison of real CSC results with those of other, deeper Chandra catalogs of the same targets and extensive simulations of blank-sky and point source populations.Comment: To be published in the Astrophysical Journal Supplement Series (Fig. 52 replaced with a version which astro-ph can convert to PDF without issues.

No observed effect of homologous recombination on influenza C virus evolution

The occurrence of homologous recombination in influenza viruses has been under some debate recently. To determine the extent of homologous recombination in influenza C virus, recombination analyses of all available gene sequences of influenza C virus were carried out. No recombination signal was found. With the previous evidence in influenza A and B viruses, it seems that homologous recombination has minimal or no effect on influenza virus evolution

Distinct mechanisms for aerenchyma formation in leaf sheaths of rice genotypes displaying a quiescence or escape strategy for flooding tolerance

Background and Aims Rice is one of the few crops able to withstand periods of partial or even complete submergence. One of the adaptive traits of rice is the constitutive presence and further development of aerenchyma which enables oxygen to be transported to submerged organs. The development of lysigenous aerenchyma is promoted by ethylene accumulating within the submerged plant tissues, although other signalling mechanisms may also co-exist. In this study, aerenchyma development was analysed in two rice (Oryza sativa) varieties, ‘FR13A’ and ‘Arborio Precoce’, which show opposite traits in flooding response in terms of internode elongation and survival. Methods The growth and survival of rice varieties under submergence was investigated in the leaf sheath of ‘FR13A’ and ‘Arborio Precoce’. The possible involvement of ethylene and reactive oxygen species (ROS) was evaluated in relation to aerenchyma formation. Cell viability and DNA fragmentation were determined by FDA/FM4-64 staining and TUNEL assay, respectively. Ethylene production was monitored by gas chromatography and by analysing ACO gene expression. ROS production was measured by using Amplex Red assay kit and the fluorescent dye DCFH2-DA. The expression of APX1 was also evaluated. AVG and DPI solutions were used to test the effect of inhibiting ethylene biosynthesis and ROS production, respectively. Key Results Both the varieties displayed constitutive lysigenous aerenchyma formation, which was further enhanced when submerged. ‘Arborio Precoce’, which is characterized by fast elongation when submerged, showed active ethylene biosynthetic machinery associated with increased aerenchymatous areas. ‘FR13A’, which harbours the Sub1A gene that limits growth during oxygen deprivation, did not show any increase in ethylene production after submersion but still displayed increased aerenchyma. Hydrogen peroxide levels increased in ‘FR13A’ but not in ‘Arborio Precoce’. Conclusions While ethylene controls aerenchyma formation in the fast-elongating ‘Arborio Precoce’ variety, in ‘FR13A’ ROS accumulation plays an important role