A multi-modal data resource for investigating topographic heterogeneity in patient-derived xenograft tumors.

Patient-derived xenografts (PDXs) are an essential pre-clinical resource for investigating tumor biology. However, cellular heterogeneity within and across PDX tumors can strongly impact the interpretation of PDX studies. Here, we generated a multi-modal, large-scale dataset to investigate PDX heterogeneity in metastatic colorectal cancer (CRC) across tumor models, spatial scales and genomic, transcriptomic, proteomic and imaging assay modalities. To showcase this dataset, we present analysis to assess sources of PDX variation, including anatomical orientation within the implanted tumor, mouse contribution, and differences between replicate PDX tumors. A unique aspect of our dataset is deep characterization of intra-tumor heterogeneity via immunofluorescence imaging, which enables investigation of variation across multiple spatial scales, from subcellular to whole tumor levels. Our study provides a benchmark data resource to investigate PDX models of metastatic CRC and serves as a template for future, quantitative investigations of spatial heterogeneity within and across PDX tumor models

Studies Needed to Address Public Health Challenges of the 2009 H1N1 Influenza Pandemic: Insights from Modeling

In light of the 2009 influenza pandemic and potential future pandemics, Maria Van Kerkhove and colleagues anticipate six public health challenges and the data needed to support sound public health decision making.The authors acknowledge support from the Bill & Melinda Gates Foundation (MDVK, CF, NMF); Royal Society (CF); Medical Research Council (MDVK, CF, PJW, NMF); EU FP7 programme (NMF); UK Health Protection Agency (PJW); US National Institutes of Health Models of Infectious Disease Agent Study program through cooperative agreement 1U54GM088588 (ML); NIH Director's Pioneer Award, DP1-OD000490-01 (DS); EU FP7 grant EMPERIE 223498 (DS); the Wellcome Trust (DS); 3R01TW008246-01S1 from Fogerty International Center and RAPIDD program from Fogerty International Center with the Science & Technology Directorate, Department of Homeland Security (SR); and the Institut de Veille Sanitaire Sanitaire funded by the French Ministry of Health (J-CD). The funders played no role in the decision to submit the article or in its preparation

An evaluation of isotopic (d2H) methods to provide estimates of avian breeding and natal dispersal

Natal and breeding dispersal represents an important component of animal demography and metapopulation theory. This phenomenon also has implications for conservation and management because understanding movements of individuals potentially allows the identification of key habitats that may be acting as population sources or sinks. Intrinsic markers such as stable isotope abundance in tissues that can be associated with provenance can provide a coarse but pragmatic solution to understanding such movements. Different methodologies have been proposed to quantify natal and breeding dispersal by using stable isotope analyses of keratinous tissues (hair, feathers), each of them with their own advantages and limitations. Here, we compared results provided by four different methods to estimate dispersal (three already published and one novel) in animals using stable isotope measurements. We used a single large dataset of feather δ2H values from golden-winged warblers (Vermivora chrysoptera) representing five different populations breeding in North America to compare model results. We propose one method as the most adequately supported by data, and we used this method to demonstrate how biological factors explaining dispersal status can be identified and geographical origins of immigrants inferred. Our results point to a generalized methodological approach to using stable isotope data to study immigration and dispersal in birds and other animals

Magnetic susceptibility of insulators from first principles

We present an {\it ab initio} approach for the computation of the magnetic susceptibility $\chi$ of insulators. The approach is applied to compute $\chi$ in diamond and in solid neon using density functional theory in the local density approximation, obtaining good agreement with experimental data. In solid neon, we predict an observable dependence of $\chi$ upon pressure.Comment: Revtex, to appear in Physical Review Lette

Quantitative Mapping of Pore Fraction Variations in Silicon Nitride Using an Ultrasonic Contact Scan Technique

An ultrasonic scan procedure using the pulse-echo contact configuration was employed to obtain maps of pore fraction variations in sintered silicon nitride samples in terms of ultrasonic material properties. Ultrasonic velocity, attenuation coefficient, and reflection coefficient images were obtained simultaneously over a broad band of frequencies (e.g., 30 to 110 MHz) by using spectroscopic analysis. Liquid and membrane (dry) coupling techniques and longitudinal and shear-wave energies were used. The major results include the following: Ultrasonic velocity (longitudinal and shear wave) images revealed and correlated with the extent of average through-thickness pore fraction variations in the silicon nitride disks. Attenuation coefficient images revealed pore fraction nonuniformity due to the scattering that occurred at boundaries between regions of high and low pore fraction. Velocity and attenuation coefficient images were each nearly identical for machined and polished disks, making the method readily applicable to machined materials. Velocity images were similar for wet and membrane coupling. Maps of apparent Poisson's ratio constructed from longitudinal and shear-wave velocities quantified Poisson's ratio variations across a silicon nitride disk. Thermal wave images of a disk indicated transient thermal behavior variations that correlated with observed variations in pore fraction and velocity and attenuation coefficients

Leveraging the ALMA Atacama Compact Array for Cometary Science: An Interferometric Survey of Comet C/2015 ER61 (PanSTARRS) and Evidence for a Distributed Source of Carbon Monosulfide

We report the first survey of molecular emission from cometary volatiles using standalone Atacama Compact Array (ACA) observations of the Atacama Large Millimeter/Submillimeter Array (ALMA) toward comet C/2015 ER61 (PanSTARRS) carried out on UT 2017 April 11 and 15, shortly after its April 4 outburst. These measurements of HCN, CS, CH$_3$OH, H$_2$CO, and HNC (along with continuum emission from dust) probed the inner coma of C/2015 ER61, revealing asymmetric outgassing and discerning parent from daughter/distributed source species. This work presents spectrally integrated flux maps, autocorrelation spectra, production rates, and parent scale lengths for each molecule, and a stringent upper limit for CO. HCN is consistent with direct nucleus release in C/2015 ER61, whereas CS, H$_2$CO, HNC, and potentially CH$_3$OH are associated with distributed sources in the coma. Adopting a Haser model, parent scale lengths determined for H$_2$CO (L$_p$ $\sim$ 2200 km) and HNC (L$_p$ $\sim$ 3300 km) are consistent with previous work in comets, whereas significant extended source production (L$_p$ $\sim$ 2000 km) is indicated for CS, suggesting production from an unknown parent in the coma. The continuum presents a point-source distribution, with a flux density implying an excessively large nucleus, inconsistent with other estimates of the nucleus size. It is best explained by the thermal emission of slowly-moving outburst ejectas, with total mass 5--8 $\times$ 10$^{10}$ kg. These results demonstrate the power of the ACA for revealing the abundances, spatial distributions, and locations of molecular production for volatiles in moderately bright comets such as C/2015 ER61

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al

The complexity of solution-free sets of integers for general linear equations

Given a linear equationL, a setAof integers isL-free ifAdoes not contain anynon-trivial solutions toL. Meeks and Treglown [6] showed that for certain kindsof linear equations, it isNP-complete to decide if a given set of integers containsa solution-free subset of a given size. Also, for equations involving three variables,they showed that the problem of determining the size of the largest solution-freesubset isAPX-hard, and that for two such equations (representing sum-free andprogression-free sets), the problem of deciding if there is a solution-free subset withat least a specified proportion of the elements is alsoNP-complete.We answer a number of questions posed by Meeks and Treglown, by extendingthe results above to all linear equations, and showing that the problems remain hardfor sets of integers whose elements are polynomially bounded in the size of the set.For most of these results, the integers can all be positive as long as the coefficientsdo not all have the same sign.We also consider the problem of counting the number of solution-free subsets ofa given set, and show that this problem is #P-complete for any linear equation inat least three variables

Bcl-xL Deamidation Is a Critical Switch in the Regulation of the Response to DNA Damage

AbstractThe therapeutic value of DNA-damaging antineoplastic agents is dependent upon their ability to induce tumor cell apoptosis while sparing most normal tissues. Here, we show that a component of the apoptotic response to these agents in several different types of tumor cells is the deamidation of two asparagines in the unstructured loop of Bcl-xL, and we demonstrate that deamidation of these asparagines imports susceptibility to apoptosis by disrupting the ability of Bcl-xL to block the proapoptotic activity of BH3 domain-only proteins. Conversely, Bcl-xL deamidation is actively suppressed in fibroblasts, and suppression of deamidation is an essential component of their resistance to DNA damage-induced apoptosis. Our results suggest that the regulation of Bcl-xL deamidation has a critical role in the tumor-specific activity of DNA-damaging antineoplastic agents