Comprehensive transcriptomic analysis of cell lines as models of primary tumors across 22 tumor types.

Cancer cell lines are a cornerstone of cancer research but previous studies have shown that not all cell lines are equal in their ability to model primary tumors. Here we present a comprehensive pan-cancer analysis utilizing transcriptomic profiles from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia to evaluate cell lines as models of primary tumors across 22 tumor types. We perform correlation analysis and gene set enrichment analysis to understand the differences between cell lines and primary tumors. Additionally, we classify cell lines into tumor subtypes in 9 tumor types. We present our pancreatic cancer results as a case study and find that the commonly used cell line MIA PaCa-2 is transcriptionally unrepresentative of primary pancreatic adenocarcinomas. Lastly, we propose a new cell line panel, the TCGA-110-CL, for pan-cancer studies. This study provides a resource to help researchers select more representative cell line models

The Phase Behavior of Mixed Lipid Membranes in Presence of the Rippled Phase

We propose a model describing liquid-solid phase coexistence in mixed lipid membranes by including explicitly the occurrence of a rippled phase. For a single component membrane, we employ a previous model in which the membrane thickness is used as an order parameter. As function of temperature, this model properly accounts for the phase behavior of the three possible membrane phases: solid, liquid and the rippled phase. Our primary aim is to explore extensions of this model to binary lipid mixtures by considering the composition dependence of important model parameters. The obtained phase diagrams show various liquid, solid and rippled phase coexistence regions, and are in quantitative agreement with the experimental ones for some specific lipid mixtures.Comment: 8pages, 5figure

Annihilation Emission from the Galactic Black Hole

Both diffuse high energy gamma-rays and an extended electron-positron annihilation line emission have been observed in the Galactic Center (GC) region. Although X-ray observations indicate that the galactic black hole Sgr A$^*$ is inactive now, we suggest that Sgr A$^*$ can become active when a captured star is tidally disrupted and matter is accreted into the black hole. As a consequence the galactic black hole could be a powerful source of relativistic protons. We are able to explain the current observed diffuse gamma-rays and the very detailed 511 keV annihilation line of secondary positrons by $p-p$ collisions of such protons, with appropriate injection times and energy. Relativistic protons could have been injected into the ambient material if the black hole captured a 50M$_\odot$ star at several tens million years ago. An alternative possibility is that the black hole continues to capture stars with $\sim$1M$_\odot$ every hundred thousand years. Secondary positrons produced by $p-p$ collisions at energies \ga 30 MeV are cooled down to thermal energies by Coulomb collisions, and annihilate in the warm neutral and ionized phases of the interstellar medium with temperatures about several eV, because the annihilation cross-section reaches its maximum at these temperatures. It takes about ten million years for the positrons to cool down to thermal temperatures so they can diffuse into a very large extended region around the Galactic center. A much more recent star capture may be also able to account for recent TeV observations within 10 pc of the galactic center as well as for the unidentified GeV gamma-ray sources found by EGRET at GC. The spectral difference between the GeV flux and the TeV flux could be explained naturally in this model as well.Comment: Accepted by ApJ on March 24, 200

Positional, Reorientational and Bond Orientational Order in DNA Mesophases

We investigate the orientational order of transverse polarization vectors of long, stiff polymer molecules and their coupling to bond orientational and positional order in high density mesophases. Homogeneous ordering of transverse polarization vector promotes distortions in the hexatic phase, whereas inhomogeneous ordering precipitates crystalization of the 2D sections with different orientations of the transverse polarization vector on each molecule in the unit cell. We propose possible scenarios for going from the hexatic phase, through the distorted hexatic phase to the crystalline phase with an orthorhombic unit cell observed experimentally for the case of DNA.Comment: 4 pages, 2 figure

Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire.

Staphylococcus aureus is both an important pathogen and a human commensal. To explore this ambivalent relationship between host and microbe, we analysed the memory humoral response against IsdB, a protein involved in iron acquisition, in four healthy donors. Here we show that in all donors a heavily biased use of two immunoglobulin heavy chain germlines generated high affinity (pM) antibodies that neutralize the two IsdB NEAT domains, IGHV4-39 for NEAT1 and IGHV1-69 for NEAT2. In contrast to the typical antibody/antigen interactions, the binding is primarily driven by the germline-encoded hydrophobic CDRH-2 motifs of IGHV1-69 and IGHV4-39, with a binding mechanism nearly identical for each antibody derived from different donors. Our results suggest that IGHV1-69 and IGHV4-39, while part of the adaptive immune system, may have evolved under selection pressure to encode a binding motif innately capable of recognizing and neutralizing a structurally conserved protein domain involved in pathogen iron acquisition

A risk-based decision policy to aid the prioritization of unsafe sidewalk locations for maintenance and rehabilitation

Air pollution and a general concern for lack of physical activity in North America have motivated governments to encourage non-motorized modes of transportation. A key infrastructure component for these forms of transportation is sidewalks. The City of Saskatoon has identified the need to formalize sidewalk management policies to demonstrate diligence for community protection regarding sidewalk safety. Prioritization of sidewalk maintenance and rehabilitation actions must be objective and minimize risk to the community. Most research on prioritization of pedestrian facilities involved new construction projects. This research proposes a decision model that prioritizes a given list of existing unsafe sidewalk locations needing maintenance or rehabilitation using a direct measure of pedestrian safety, namely, quality-adjusted life years lost per year. A decision model was developed for prioritizing a given list of unsafe sidewalk locations, aiding maintenance and rehabilitation decisions by providing the associated risk to pedestrian safety. The model used data mostly from high quality sources that had already been collected and validated. Probabilities and estimations were used to produce value-added decision policy. The decision analysis framework applied probability and multi-attribute utility theories. This study differed from other research due to the inclusion of age and gender groups. Total average daily population of the city was estimated. This population was distributed to sidewalk locations using probabilities for trip purposes and a location’s ability to attract people relative to the city total. Then trip injury events were predicted. Age and gender distribution and trip injury type estimations were used to determine the impact of those injuries on quality of life.There exist much observable high quality data that can be used as indicators of unknown or unobserved events. A decision policy was developed that prioritizes unsafe sidewalk locations based on the direct safety impact on pedestrians. Results showed that quality-adjusted life years lost per year sufficiently prioritized a given list of unsafe sidewalk locations. It was demonstrated that the use of conditional probabilities (n=594) allowed for the ability to abstract data representing a different source population to another. Average daily population confined and distributed within the city boundary minimized problems of accuracy. Gender-age distribution was important for differentiating the risk at unsafe sidewalk locations. Concepts from this research provide for possible extension to the development of sidewalk service levels and sidewalk priority maps and for risk assessment of other public services

Generation of small-scale structures in the developed turbulence

The Navier-Stokes equation for incompressible liquid is considered in the limit of infinitely large Reynolds number. It is assumed that the flow instability leads to generation of steady-state large-scale pulsations. The excitation and evolution of the small-scale turbulence is investigated. It is shown that the developed small-scale pulsations are intermittent. The maximal amplitude of the vorticity fluctuations is reached along the vortex filaments. Basing on the obtained solution, the pair correlation function in the limit $r\to 0$ is calculated. It is shown that the function obeys the Kolmogorov law $r^{2/3}$.Comment: 18 page

Bifurcations in annular electroconvection with an imposed shear

We report an experimental study of the primary bifurcation in electrically-driven convection in a freely suspended film. A weakly conducting, submicron thick smectic liquid crystal film was supported by concentric circular electrodes. It electroconvected when a sufficiently large voltage $V$ was applied between its inner and outer edges. The film could sustain rapid flows and yet remain strictly two-dimensional. By rotation of the inner electrode, a circular Couette shear could be independently imposed. The control parameters were a dimensionless number ${\cal R}$, analogous to the Rayleigh number, which is $\propto V^2$ and the Reynolds number ${\cal R}e$ of the azimuthal shear flow. The geometrical and material properties of the film were characterized by the radius ratio $\alpha$, and a Prandtl-like number ${\cal P}$. Using measurements of current-voltage characteristics of a large number of films, we examined the onset of electroconvection over a broad range of $\alpha$, ${\cal P}$ and ${\cal R}e$. We compared this data quantitatively to the results of linear stability theory. This could be done with essentially no adjustable parameters. The current-voltage data above onset were then used to infer the amplitude of electroconvection in the weakly nonlinear regime by fitting them to a steady-state amplitude equation of the Landau form. We show how the primary bifurcation can be tuned between supercritical and subcritical by changing $\alpha$ and ${\cal R}e$.Comment: 17 pages, 12 figures. Submitted to Phys. Rev. E. Minor changes after refereeing. See also http://mobydick.physics.utoronto.c

Structural mapping in statistical word problems: A relational reasoning approach to Bayesian inference

Presenting natural frequencies facilitates Bayesian inferences relative to using percentages. Nevertheless, many people, including highly educated and skilled reasoners, still fail to provide Bayesian responses to these computationally simple problems. We show that the complexity of relational reasoning (e.g., the structural mapping between the presented and requested relations) can help explain the remaining difficulties. With a non-Bayesian inference that required identical arithmetic but afforded a more direct structural mapping, performance was universally high. Furthermore, reducing the relational demands of the task through questions that directed reasoners to use the presented statistics, as compared with questions that prompted the representation of a second, similar sample, also significantly improved reasoning. Distinct error patterns were also observed between these presented- and similar-sample scenarios, which suggested differences in relational-reasoning strategies. On the other hand, while higher numeracy was associated with better Bayesian reasoning, higher-numerate reasoners were not immune to the relational complexity of the task. Together, these findings validate the relational-reasoning view of Bayesian problem solving and highlight the importance of considering not only the presented task structure, but also the complexity of the structural alignment between the presented and requested relations

Novel associations for hypothyroidism include known autoimmune risk loci

Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the first large genome-wide association study of hypothyroidism, in 2,564 cases and 24,448 controls from the customer base of 23andMe, Inc., a personal genetics company. We identify four genome-wide significant associations, two of which are well known to be involved with a large spectrum of autoimmune diseases: rs6679677 near _PTPN22_ and rs3184504 in _SH2B3_ (p-values 3.5e-13 and 3.0e-11, respectively). We also report associations with rs4915077 near _VAV3_ (p-value 8.3e-11), another gene involved in immune function, and rs965513 near _FOXE1_ (p-value 3.1e-14). Of these, the association with _PTPN22_ confirms a recent small candidate gene study, and _FOXE1_ was previously known to be associated with thyroid-stimulating hormone (TSH) levels. Although _SH2B3_ has been previously linked with a number of autoimmune diseases, this is the first report of its association with thyroid disease. The _VAV3_ association is novel. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the four genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.1