P-rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments

Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes

The conditional permutation test for independence while controlling for confounders

We propose a general new method, the conditional permutation test, for testing the conditional independence of variables $X$ and $Y$ given a potentially high-dimensional random vector $Z$ that may contain confounding factors. The proposed test permutes entries of $X$ non-uniformly, so as to respect the existing dependence between $X$ and $Z$ and thus account for the presence of these confounders. Like the conditional randomization test of Cand\`es et al. (2018), our test relies on the availability of an approximation to the distribution of $X \mid Z$. While Cand\`es et al. (2018)'s test uses this estimate to draw new $X$ values, for our test we use this approximation to design an appropriate non-uniform distribution on permutations of the $X$ values already seen in the true data. We provide an efficient Markov Chain Monte Carlo sampler for the implementation of our method, and establish bounds on the Type I error in terms of the error in the approximation of the conditional distribution of $X\mid Z$, finding that, for the worst case test statistic, the inflation in Type I error of the conditional permutation test is no larger than that of the conditional randomization test. We validate these theoretical results with experiments on simulated data and on the Capital Bikeshare data set

Computational Cancer Biology: An Evolutionary Perspective

ISSN:1553-734XISSN:1553-735

The Spin Structure of the Nucleon

We present an overview of recent experimental and theoretical advances in our understanding of the spin structure of protons and neutrons.Comment: 84 pages, 29 figure

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Thinking about a limited future enhances the positivity of younger and older adults’ recall: support for socioemotional selectivity theory

Compared with younger adults, older adults have a relative preference to attend to and remember positive over negative information. This is known as the “positivity effect,” and researchers have typically evoked socioemotional selectivity theory to explain it. According to socioemotional selectivity theory, as people get older they begin to perceive their time left in life as more limited. These reduced time horizons prompt older adults to prioritize achieving emotional gratification and thus exhibit increased positivity in attention and recall. Although this is the most commonly cited explanation of the positivity effect, there is currently a lack of clear experimental evidence demonstrating a link between time horizons and positivity. The goal of the current research was to address this issue. In two separate experiments, we asked participants to complete a writing activity, which directed them to think of time as being either limited or expansive (Experiments 1 and 2) or did not orient them to think about time in a particular manner (Experiment 2). Participants were then shown a series of emotional pictures, which they subsequently tried to recall. Results from both studies showed that regardless of chronological age, thinking about a limited future enhanced the relative positivity of participants’ recall. Furthermore, the results of Experiment 2 showed that this effect was not driven by changes in mood. Thus, the fact that older adults’ recall is typically more positive than younger adults’ recall may index naturally shifting time horizons and goals with age

The potential of optical proteomic technologies to individualize prognosis and guide rational treatment for cancer patients

Genomics and proteomics will improve outcome prediction in cancer and have great potential to help in the discovery of unknown mechanisms of metastasis, ripe for therapeutic exploitation. Current methods of prognosis estimation rely on clinical data, anatomical staging and histopathological features. It is hoped that translational genomic and proteomic research will discriminate more accurately than is possible at present between patients with a good prognosis and those who carry a high risk of recurrence. Rational treatments, targeted to the specific molecular pathways of an individual's high-risk tumor, are at the core of tailored therapy. The aim of targeted oncology is to select the right patient for the right drug at precisely the right point in their cancer journey. Optical proteomics uses advanced optical imaging technologies to quantify the activity states of and associations between signaling proteins by measuring energy transfer between fluorophores attached to specific proteins. Förster resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM) assays are suitable for use in cell line models of cancer, fresh human tissues and formalin-fixed paraffin-embedded tissue (FFPE). In animal models, dynamic deep tissue FLIM/FRET imaging of cancer cells in vivo is now also feasible. Analysis of protein expression and post-translational modifications such as phosphorylation and ubiquitination can be performed in cell lines and are remarkably efficiently in cancer tissue samples using tissue microarrays (TMAs). FRET assays can be performed to quantify protein-protein interactions within FFPE tissue, far beyond the spatial resolution conventionally associated with light or confocal laser microscopy. Multivariate optical parameters can be correlated with disease relapse for individual patients. FRET-FLIM assays allow rapid screening of target modifiers using high content drug screens. Specific protein-protein interactions conferring a poor prognosis identified by high content tissue screening will be perturbed with targeted therapeutics. Future targeted drugs will be identified using high content/throughput drug screens that are based on multivariate proteomic assays. Response to therapy at a molecular level can be monitored using these assays while the patient receives treatment: utilizing re-biopsy tumor tissue samples in the neoadjuvant setting or by examining surrogate tissues. These technologies will prove to be both prognostic of risk for individuals when applied to tumor tissue at first diagnosis and predictive of response to specifically selected targeted anticancer drugs. Advanced optical assays have great potential to be translated into real-life benefit for cancer patients

Railway transportation as a serious source of organic and inorganic pollution

Polycyclic aromatic hydrocarbons and heavy metal (Pb, Cd, Cu, Zn, Hg, Fe, Co, Cr, Mo) contents were established in soil and plant samples collected in different areas of the railway junction Iława Główna, Poland. Soil and plant samples were collected in four functional parts of the junction, i.e. the loading ramp, main track within platform area, rolling stock cleaning bay and the railway siding. It was found that all the investigated areas were strongly contaminated with polycyclic aromatic hydrocarbons (PAHs). The PAH contamination of the soil was the highest in the railway siding and in the platform area (59,508 and 49,670 μg kg−1, respectively). In the loading ramp and cleaning bay, the PAH concentration in soil was lower but still relatively very high (17,948 and 15,376 μg kg−1, respectively). The contamination in the railway siding exceeded the average control level up to about 80 times. In the soil of all the investigated areas, four- and five-ring PAHs prevailed. The concentrations of PAHs were determined in four dominating species of plants found at the junction. The highest concentration was found in the aerial parts of Taraxacum officinale (22,492 μg kg−1) growing in the cleaning bay. The comparison of the soil contamination with PAHs in the investigated railway junction showed a very significant increase of the PAHs level since 1995. It was found that the heavy metal contamination was also very high. Pb, Zn, Hg and Cd were established at the highest levels in the railway siding area, whereas Fe concentration was the highest in the platform area. A significant increase in mercury content was observed in the cleaning bay area. The investigations proved very significant increase of contamination with PAHs and similar heavy metals contamination in comparison with the concentration determined in the same areas 13 years ago