Shortest path or anchor-based route choice: a large-scale empirical analysis of minicab routing in London

Understanding and modelling route choice behaviour is central to predicting the formation and propagation of urban road congestion. Yet within conventional literature disagreements persist around the nature of route choice behaviour, and how it should be modelled. In this paper, both the shortest path and anchor-based perspectives on route choice behaviour are explored through an empirical analysis of nearly 700,000 minicab routes across London, United Kingdom. In the first set of analyses, the degree of similarity between observed routes and possible shortest paths is established. Shortest paths demonstrate poor performance in predicting both observed route choice and characteristics. The second stage of analysis explores the influence of specific urban features, named anchors, in route choice. These analyses show that certain features attract more route choices than would be expected were individuals choosing route based on cost minimisation alone. Instead, the results indicate that major urban features form the basis of route choice planning – being selected disproportionately more often, and causing asymmetry in route choice volumes by direction of travel. At a finer scale, decisions made at minor road features are furthermore demonstrated to influence routing patterns. The results indicate a need to revisit the basis of how routes are modelled, shifting from the shortest path perspective to a mechanism structured around urban features. In concluding, the main trends are synthesised within an initial framework for route choice modelling, and presents potential extensions of this research

Interactions between rail and road safety in Great Britain

This paper discusses the results of an investigation into ways in which the safety risks of travel on road and rail interact with each other in Great Britain, other than through physical contact such as at level crossings. The two main foci of the paper are: (1) an analysis of the 'whole journey' risks of journeys for which the national rail system is the main mode, but which also include stages by other transport modes to provide access to the railway system: and (2) an analysis of the effect on safety risk of inter-modal transfers between rail and road. On (1), walking to and from stations was estimated to account on average for 65% of the overall door-to-door risk of being killed on rail journeys: the rail system itself accounts for 21% of the risk, and other access modes account for the remaining 14%. The average distance walked to and from stations is 0.9 km per rail journey, and this walking accounts for 5% of all walking nationally. On (2), it was found that increasing rail fares to fund railway safety measures may lead passengers to switch from rail to car, but for most sensible rail safety measures, the additional risks from such diversions are small compared with the intended rail safety benefits. However, for high-cost rail safety measures funded by passengers, the additional risks from diversions may be of the same order as the intended safety benefits. The last section of the paper explores the effects of variations in the casualty rates of rail users as pedestrians and car users. because their road risks may be different from those of all road users. Such variations could alter the detailed conclusions of the paper, but the scale of such effects appears to be modest. (c) 2008 Elsevier Ltd. All rights reserved

Duffy antigen receptor for chemokines mediates chemokine endocytosis through a macropinocytosis-like process in endothelial cells

Background: The Duffy antigen receptor for chemokines (DARC) shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. However, the mechanism of chemokine endocytosis by DARC remains unclear. Methodology/Principal Findings: We investigated the role of several endocytic pathways in DARC-mediated ligand internalization. Here we report that, although DARC co-localizes with caveolin-1 in endothelial cells, caveolin-1 is dispensable for DARC-mediated 125I-CXCL1 endocytosis as knockdown of caveolin-1 failed to inhibit ligand internalization. 125I-CXCL1 endocytosis by DARC was also independent of clathrin and flotillin-1 but required cholesterol and was, in part, inhibited by silencing Dynamin II expression. 125I-CXCL1 endocytosis was inhibited by amiloride, cytochalasin D, and the PKC inhibitor Gö6976 whereas Platelet Derived Growth Factor (PDGF) enhanced ligand internalization through DARC. The majority of DARC-ligand interactions occurred on the endothelial surface, with DARC identified along plasma membrane extensions with the appearance of ruffles, supporting the concept that DARC provides a high affinity scaffolding function for surface retention of chemokines on endothelial cells. Conclusions/Significance: These results show DARC-mediated chemokine endocytosis occurs through a macropinocytosis-like process in endothelial cells and caveolin-1 is dispensable for CXCL1 internalization. © 2011 Zhao et al

Lovastatin Inhibits VEGFR and AKT Activation: Synergistic Cytotoxicity in Combination with VEGFR Inhibitors

BACKGROUND: In a recent study, we demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to inhibit the function of the epidermal growth factor receptor (EGFR). Lovastatin attenuated ligand-induced receptor activation and downstream signaling through the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in a variety of tumor derived cell lines. The vascular endothelial growth factor receptor (VEGFR) and EGFR share similar activation, internalization and downstream signaling characteristics. METHODOLOGY/PRINCIPAL FINDINGS: The VEGFRs, particularly VEGFR-2 (KDR, Flt-1), play important roles in regulating tumor angiogenesis by promoting endothelial cell proliferation, survival and migration. Certain tumors, such as malignant mesothelioma (MM), also express both the VEGF ligand and VEGFRs that act in an autocrine loop to directly stimulate tumor cell growth and survival. In this study, we have shown that lovastatin inhibits ligand-induced VEGFR-2 activation through inhibition of receptor internalization and also inhibits VEGF activation of AKT in human umbilical vein endothelial cells (HUVEC) and H28 MM cells employing immunofluorescence and Western blotting. Combinations of lovastatin and a VEGFR-2 inhibitor showed more robust AKT inhibition than either agent alone in the H28 MM cell line. Furthermore, combining 5 µM lovastatin treatment, a therapeutically relevant dose, with two different VEGFR-2 inhibitors in HUVEC and the H28 and H2052 mesothelioma derived cell lines demonstrated synergistic cytotoxicity as demonstrated by MTT cell viability and flow cytometric analyses. CONCLUSIONS/SIGNIFICANCE: These results highlight a novel mechanism by which lovastatin can regulate VEGFR-2 function and a potential therapeutic approach for MM through combining statins with VEGFR-2 inhibitors

Genome Wide Association Identifies PPFIA1 as a Candidate Gene for Acute Lung Injury Risk Following Major Trauma

Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypoxemia and pulmonary infiltrates in patients with critical illness. We conducted the first investigation to use the genome wide association (GWA) approach to identify putative risk variants for ALI. Genome wide genotyping was performed using the Illumina Human Quad 610 BeadChip. We performed a two-stage GWA study followed by a third stage of functional characterization. In the discovery phase (Phase 1), we compared 600 European American trauma-associated ALI cases with 2266 European American population-based controls. We carried forward the top 1% of single nucleotide polymorphisms (SNPs) at p<0.01 to a replication phase (Phase 2) comprised of a nested case-control design sample of 212 trauma-associated ALI cases and 283 at-risk trauma non-ALI controls from ongoing cohort studies. SNPs that replicated at the 0.05 level in Phase 2 were subject to functional validation (Phase 3) using expression quantitative trait loci (eQTL) analyses in stimulated B-lymphoblastoid cell lines (B-LCL) in family trios. 159 SNPs from the discovery phase replicated in Phase 2, including loci with prior evidence for a role in ALI pathogenesis. Functional evaluation of these replicated SNPs revealed rs471931 on 11q13.3 to exert a cis-regulatory effect on mRNA expression in the PPFIA1 gene (p = 0.0021). PPFIA1 encodes liprin alpha, a protein involved in cell adhesion, integrin expression, and cell-matrix interactions. This study supports the feasibility of future multi-center GWA investigations of ALI risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research